Submissions for variant NM_000059.4(BRCA2):c.1225G>A (p.Glu409Lys)

gnomAD frequency: 0.00001  dbSNP: rs80358416

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043761	SCV000071774	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000164321	SCV000214952	likely benign	Hereditary cancer-predisposing syndrome	2018-10-03	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.
PreventionGenetics, part of Exact Sciences	RCV000679154	SCV000805649	uncertain significance	not provided	2017-10-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164321	SCV000911863	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 409 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. In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 2/53461 unaffected controls, showing inconclusive association with disease (OR=0.442 (95%CI 0.04 to 4.876); p-value=0.603; Leiden Open Variation Database DB-ID BRCA2_007803) (PMID: 33471991). This variant has been identified in 3/245760 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251342	SCV001426906	uncertain significance	not specified	2020-07-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1225G>A (p.Glu409Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250188 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1225G>A has been reported in the literature in one individual affected with Glioblastomas (Xiu_2016). The report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164321	SCV003849923	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679154	SCV004219499	uncertain significance	not provided	2023-08-04	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with glioblastoma (PMID: 26933808 (2016)). In a large-scale breast cancer association study, the variant was observed in a breast cancer case and in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The frequency of this variant in the general population, 0.000031 (4/128766 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000112895	SCV004846884	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 409 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. In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 2/53461 unaffected controls, showing inconclusive association with disease (OR=0.442 (95%CI 0.04 to 4.876); p-value=0.603; Leiden Open Variation Database DB-ID BRCA2_007803) (PMID: 33471991). This variant has been identified in 3/245760 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112895	SCV000145834	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing