617-768-8500 confidence: 1.0 position: {"char": 4369} context:
ry for Molecular Medicine at: [email protected] or
617-768-8500.
DETAILED VARIANT INFORMATION (VARIANTS RELEVANT
Blood, Peripheral
Sex: Male Referring facility: Double Helix Hospital Lab Control Number: ABC123
Race/Ethnicity: White Referring physician: Dr. DNA Received: 01/24/2014
Family #: F012345 Copies to: CGC Page: 1 of 4
Test(s) performed: Whole genome sequencing
Indication for test: Clinical diagnosis and family history of DCM with arrhythmia
APPROACH
Sequencing of this individual's genome was performed and the data was analyzed to identify previously reported and novel variants in (1)
335 genes that have been previously implicated in various cardiac diseases and myopathies (see Supplement for a list of genes and coverage
information); and (2) variants classified as disease-causing in public databases that confidence: 0.81 position: {"char": 84} context:
Blood, Peripheral
Sex: Male Referring facility: Double Helix Hospital Lab Control Number: ABC123
Race/Ethnicity: White Referring physician: Dr. DNA Received: 01/24/2014
Family #: F012345 Copies to: CGC Page: 1 of 4
Test(s) performed: Whole genome sequencing
Indication for test: Clinical diagnosis and family history of DCM with arrhythmia
APPROACH
Sequencing of this individual's genome was performed and the data was analyzed to identify previously reported and novel variants in (1)
335 genes that have been previously implicated in various cardiac diseases and myopathies (see Supplement for a list of genes and coverage
information); and (2) variants classified as disease-causing in public databases that
Disease or Phenotype Inheritance Classification
MUTYH
NM_012222
c.1428_1430del
p.Glu477del
Het. Exon 14 MUTYH-associated adenomatous polyposis
Autosomal
recessive Pathogenic
RESULT: Positive
Findings explain patient phenotype, Incidental findings identified
LABORATORY FOR MOLECULAR MEDICINE
65 Landsdowne St, Cambridge, MA 02139
Phone: (617) 768-8500 / Fax: (617) 768-8513
http://pcpgm.partners.org/lmm
http://pcpgm.partners.org/lmm
Accession ID: PM-XX-12345
Name: DOE, JOHN
Family #: F012345
Page: 2 of 4
LABORATORY FOR MOLECULAR MEDICINE
65 Landsdowne St, Cambridge, MA 02139
Phone: (617) 768-8500 / Fax: (617) 768-8513
http://pcpgm.partners.org/lmm
RECOMMENDATIONS
These results should be interpreted in the context of the patient’s medical evaluation, family history, and racial/ethnic background. Please
note that confidence: 0.79 position: {"char": 3148} context:
Disease or Phenotype Inheritance Classification
MUTYH
NM_012222
c.1428_1430del
p.Glu477del
Het. Exon 14 MUTYH-associated adenomatous polyposis
Autosomal
recessive Pathogenic
RESULT: Positive
Findings explain patient phenotype, Incidental findings identified
LABORATORY FOR MOLECULAR MEDICINE
65 Landsdowne St, Cambridge, MA 02139
Phone: (617) 768-8500 / Fax: (617) 768-8513
http://pcpgm.partners.org/lmm
http://pcpgm.partners.org/lmm
Accession ID: PM-XX-12345
Name: DOE, JOHN
Family #: F012345
Page: 2 of 4
LABORATORY FOR MOLECULAR MEDICINE
65 Landsdowne St, Cambridge, MA 02139
Phone: (617) 768-8500 / Fax: (617) 768-8513
http://pcpgm.partners.org/lmm
RECOMMENDATIONS
These results should be interpreted in the context of the patient’s medical evaluation, family history, and racial/ethnic background. Please
note that
Exon 1 Dilated Cardiomyopathy
Autosomal
dominant
Pathogenic
OTHER VARIANTS OF MEDICAL SIGNIFICANCE (INCIDENTAL FINDINGS)
Incidental findings are variants of medical significance that are not associated with the individual's reported indication. Please note that the
presence of pathogenic variants in genes with incomplete coverage or in genes not examined cannot be fully excluded. Please contact the
Laboratory for Molecular Medicine for coverage information on genes analyzed for incidental findings.
Monogenic Disease Risk
This test did NOT identify genetic variants that may be responsible for other diseases unrelated to this individual’s clinical presentation.
Please see limitations for more detail.
Carrier Status confidence: 0.79 position: {"char": 2069} context:
Exon 1 Dilated Cardiomyopathy
Autosomal
dominant
Pathogenic
OTHER VARIANTS OF MEDICAL SIGNIFICANCE (INCIDENTAL FINDINGS)
Incidental findings are variants of medical significance that are not associated with the individual's reported indication. Please note that the
presence of pathogenic variants in genes with incomplete coverage or in genes not examined cannot be fully excluded. Please contact the
Laboratory for Molecular Medicine for coverage information on genes analyzed for incidental findings.
Monogenic Disease Risk
This test did NOT identify genetic variants that may be responsible for other diseases unrelated to this individual’s clinical presentation.
Please see limitations for more detail.
Carrier Status
NHLBI ESP; and (4) previously reported and novel variants in 56 genes predicted to
be of medical significance by the American College of Medical Genetics (Green 2013), which may be unrelated to the patient phenotype
(incidental findings). All genes relevant to the indication had adequate coverage (>95% at 8X). Please note that the presence of pathogenic
variants in genes not analyzed or with incomplete coverage cannot be fully excluded.
VARIANTS RELEVANT TO INDICATION FOR TESTING
One pathogenic variant in LMNA was identified in this individual. The LMNA gene is strongly associated with DCM, which is consistent with
the reported clinical diagnosis. No other variants confidence: 0.78 position: {"char": 1151} context:
NHLBI ESP; and (4) previously reported and novel variants in 56 genes predicted to
be of medical significance by the American College of Medical Genetics (Green 2013), which may be unrelated to the patient phenotype
(incidental findings). All genes relevant to the indication had adequate coverage (>95% at 8X). Please note that the presence of pathogenic
variants in genes not analyzed or with incomplete coverage cannot be fully excluded.
VARIANTS RELEVANT TO INDICATION FOR TESTING
One pathogenic variant in LMNA was identified in this individual. The LMNA gene is strongly associated with DCM, which is consistent with
the reported clinical diagnosis. No other variants
first-degree relative has a 50% (or 1 in 2) chance of inheriting a variant and its risk for cardiomyopathy. Disease penetrance and
severity can vary due to modifier genes and/or environmental factors. The significance of a variant should therefore be interpreted in the
context of the individual's clinical manifestations.
DETAILED VARIANT INFORMATION (INCIDENTAL FINDINGS)
Monogenic Disease Risk
This test did NOT identify genetic variants that may be responsible for other diseases unrelated to this individual’s clinical presentation.
Please see limitations for more detail.
Carrier Status
Gene &
Transcript Variant
Allele
State Location Disease or Phenotype Inheritance Classification
MUTYH
NM_012222
c confidence: 0.77 position: {"char": 5852} context:
first-degree relative has a 50% (or 1 in 2) chance of inheriting a variant and its risk for cardiomyopathy. Disease penetrance and
severity can vary due to modifier genes and/or environmental factors. The significance of a variant should therefore be interpreted in the
context of the individual's clinical manifestations.
DETAILED VARIANT INFORMATION (INCIDENTAL FINDINGS)
Monogenic Disease Risk
This test did NOT identify genetic variants that may be responsible for other diseases unrelated to this individual’s clinical presentation.
Please see limitations for more detail.
Carrier Status
Gene &
Transcript Variant
Allele
State Location Disease or Phenotype Inheritance Classification
MUTYH
NM_012222
c
LMM) based upon its frequency in patients, segregation studies, and
functional evidence.
http://pcpgm.partners.org/lmm
mailto:[email protected]
http://www.ncbi.nlm.nih.gov/books/NBK1674/
Accession ID: PM-XX-12345
Name: DOE, JOHN
Family #: F012345
Page: 3 of 4
LABORATORY FOR MOLECULAR MEDICINE
65 Landsdowne St, Cambridge, MA 02139
Phone: (617) 768-8500 / Fax: (617) 768-8513
http://pcpgm.partners.org/lmm
DISEASE INFORMATION: MUTYH-related adenomatous polyposis (or autosomal recessive familial adenomatous polyposis; OMIM#
608456) is caused by biallelic mutations in MUTYH and is characterized by multiple colorectal adenomas and a high risk of colorectal
cancer (43% to almost 100% in the absence of timely surveillance). Although typically associated confidence: 0.76 position: {"char": 8150} context:
LMM) based upon its frequency in patients, segregation studies, and
functional evidence.
http://pcpgm.partners.org/lmm
mailto:[email protected]
http://www.ncbi.nlm.nih.gov/books/NBK1674/
Accession ID: PM-XX-12345
Name: DOE, JOHN
Family #: F012345
Page: 3 of 4
LABORATORY FOR MOLECULAR MEDICINE
65 Landsdowne St, Cambridge, MA 02139
Phone: (617) 768-8500 / Fax: (617) 768-8513
http://pcpgm.partners.org/lmm
DISEASE INFORMATION: MUTYH-related adenomatous polyposis (or autosomal recessive familial adenomatous polyposis; OMIM#
608456) is caused by biallelic mutations in MUTYH and is characterized by multiple colorectal adenomas and a high risk of colorectal
cancer (43% to almost 100% in the absence of timely surveillance). Although typically associated
with disease in 8 affected relatives (Wang 2006, Wu 2010). It has not been identified in large
population studies. Functional studies (in vitro) suggest an effect on protein function and mice carrying the variant exhibited clinical
features of DCM (Wang 2006, Lu 2010, Sun 2010). In summary, this variant meets our criteria to be classified as pathogenic
(http://pcpgm.partners.org/LMM) based upon segregation studies, absence from controls, and functional evidence.
DISEASE INFORMATION: LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and reduced
systolic function frequently accompanied by significant conduction system disease and/or myopathy. Adapted from GeneReviews:
http://www.ncbi.nlm confidence: 0.76 position: {"char": 4937} context:
with disease in 8 affected relatives (Wang 2006, Wu 2010). It has not been identified in large
population studies. Functional studies (in vitro) suggest an effect on protein function and mice carrying the variant exhibited clinical
features of DCM (Wang 2006, Lu 2010, Sun 2010). In summary, this variant meets our criteria to be classified as pathogenic
(http://pcpgm.partners.org/LMM) based upon segregation studies, absence from controls, and functional evidence.
DISEASE INFORMATION: LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and reduced
systolic function frequently accompanied by significant conduction system disease and/or myopathy. Adapted from GeneReviews:
http://www.ncbi.nlm
age of about 50 years, colon cancer develops in some individuals with biallelic MUTYH
mutations in the absence of polyposis. Duodenal adenomas are found in 17%-25% of individuals; the lifetime risk of duodenal cancer is
about 4%. Individuals may also have modestly increased risk for rather late-onset malignancies of the ovary, bladder, skin, breast and
endometrial cancer. Although MUTYH-related familial adenomatous polyposis is a recessive disorder, studies suggest that heterozygous
carriers of MUTYH variants may have higher risk for colorectal cancer compared to the general population (OR: 2-3) (Jenkins 2006, Jones
2009). (Adapted from GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK107219/)
PREVALENCE confidence: 0.76 position: {"char": 8985} context:
age of about 50 years, colon cancer develops in some individuals with biallelic MUTYH
mutations in the absence of polyposis. Duodenal adenomas are found in 17%-25% of individuals; the lifetime risk of duodenal cancer is
about 4%. Individuals may also have modestly increased risk for rather late-onset malignancies of the ovary, bladder, skin, breast and
endometrial cancer. Although MUTYH-related familial adenomatous polyposis is a recessive disorder, studies suggest that heterozygous
carriers of MUTYH variants may have higher risk for colorectal cancer compared to the general population (OR: 2-3) (Jenkins 2006, Jones
2009). (Adapted from GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK107219/)
PREVALENCE
may change over time if more information becomes available. Reinterpretation of
exome sequencing data is recommended on an annual basis and may be requested by a medical provider. For questions about this report, or
for assistance in locating nearby genetic counseling services, please contact the Laboratory for Molecular Medicine at: [email protected] or
617-768-8500.
DETAILED VARIANT INFORMATION (VARIANTS RELEVANT TO INDICATION FOR TESTING)
Gene &
Transcript Variant
Allele
State Location Disease or Phenotype Inheritance Classification
LMNA
NM_00112233.5
c.244G>A
p.Glu82Lys
Het.
(Mat.)
Exon 1 Dilated Cardiomyopathy
Autosomal
dominant
Pathogenic
Genomic Position Variant Frequency
GRCh37 Chr11: g.47364249G>A Not confidence: 0.74 position: {"char": 4013} context:
may change over time if more information becomes available. Reinterpretation of
exome sequencing data is recommended on an annual basis and may be requested by a medical provider. For questions about this report, or
for assistance in locating nearby genetic counseling services, please contact the Laboratory for Molecular Medicine at: [email protected] or
617-768-8500.
DETAILED VARIANT INFORMATION (VARIANTS RELEVANT TO INDICATION FOR TESTING)
Gene &
Transcript Variant
Allele
State Location Disease or Phenotype Inheritance Classification
LMNA
NM_00112233.5
c.244G>A
p.Glu82Lys
Het.
(Mat.)
Exon 1 Dilated Cardiomyopathy
Autosomal
dominant
Pathogenic
Genomic Position Variant Frequency
GRCh37 Chr11: g.47364249G>A Not
that the p.Glu477del variant may impact protein
function (Dagostino 2010, Goto 2010, Molatore 2010). This variant has also been identified in 10/66728 European and 4/16512 of South
Asian chromosomes by the Exome Aggregation Consortium, including one homozygote (ExAC, http://exac.broadinstitute.org). Please note
that variants associated with diseases that have reduced penetrance and late age-of-onset may be present at a low frequency in large
population studies; therefore the frequency of this variant is consistent with the known prevalance and penetrance of this disease. In
summary, this variant meets our criteria to be classified as pathogenic for MUTYH-associated adenomatous polyposis confidence: 0.68 position: {"char": 7375} context:
that the p.Glu477del variant may impact protein
function (Dagostino 2010, Goto 2010, Molatore 2010). This variant has also been identified in 10/66728 European and 4/16512 of South
Asian chromosomes by the Exome Aggregation Consortium, including one homozygote (ExAC, http://exac.broadinstitute.org). Please note
that variants associated with diseases that have reduced penetrance and late age-of-onset may be present at a low frequency in large
population studies; therefore the frequency of this variant is consistent with the known prevalance and penetrance of this disease. In
summary, this variant meets our criteria to be classified as pathogenic for MUTYH-associated adenomatous polyposis