Submissions for variant NM_000059.4(BRCA2):c.8417C>T (p.Ser2806Leu)

gnomAD frequency: 0.00001  dbSNP: rs587782785

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132333	SCV000187421	likely benign	Hereditary cancer-predisposing syndrome	2020-01-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000679192	SCV000279530	likely benign	not provided	2021-04-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25682074, 25925381, 27978560, 31131967, 29470806, 32531196, 32377563)
Counsyl	RCV000411091	SCV000489118	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-08-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086081	SCV000560391	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132333	SCV000683964	likely benign	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000411091	SCV000744539	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679192	SCV000805778	uncertain significance	not provided	2017-10-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170974	SCV001333634	uncertain significance	Breast and/or ovarian cancer	2019-08-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192608	SCV001360850	likely benign	not specified	2023-08-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8417C>T (p.Ser2806Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251380 control chromosomes, predominantly at a frequency of 0.0021 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.8417C>T has been reported in the literature as a VUS in settings of multigene panel testing among individuals undergoing testing for colorectal/breast/ovarian cancer (example, Pearlman_2016, Wong-Brown_2015, Zidan_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Richardson_2021, Hu_2022). These results showed no damaging effect of this variant on homology directed repair (HDR) activity. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). The following publications have been ascertained in the context of this evaluation (PMID: 25682074, 27978560, 28828701, 33609447, 35736817). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679192	SCV001469723	likely benign	not provided	2019-11-25	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000679192	SCV001905859	uncertain significance	not provided		no assertion criteria provided	clinical testing