ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8417C>T (p.Ser2806Leu) (rs587782785)

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Total submissions: 10
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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 General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
GeneDx RCV000679192 SCV000279530 uncertain significance not provided 2018-06-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8417C>T at the cDNA level, p.Ser2806Leu (S2806L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). Using alternate nomenclature, this variant would be defined as BRCA2 8645C>T. This variant was observed in at least one individual with breast cancer and another with rectal cancer (Wong-Brown 2015, Pearlman 2016). BRCA2 Ser2806Leu was observed at an allele frequency of 0.21% (63/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located at a DSS1 contacting residue within the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ser2806Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000411091 SCV000489118 uncertain significance Breast-ovarian cancer, familial 2 2016-08-22 criteria provided, single submitter clinical testing
Invitae RCV001086081 SCV000560391 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-11 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132333 SCV000683964 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-19 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 2806 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 64/251380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000411091 SCV000744539 uncertain significance Breast-ovarian cancer, familial 2 2017-05-31 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics 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 2018-06-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192608 SCV001360850 likely benign not specified 2019-05-20 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 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 in individuals affected with colorectal cancer and breast cancer without strong evidence of causality (Pearlman_2016, Wong-Brown_2015). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (6x uncertain significance and 1x likely benign). 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

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