Submissions for variant NM_000059.4(BRCA2):c.2122T>A (p.Ser708Thr)

gnomAD frequency: 0.00001  dbSNP: rs80358488

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043947	SCV000071960	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 708 of the BRCA2 protein (p.Ser708Thr). This variant is present in population databases (rs80358488, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer, colon cancer, and ovarian cancer (PMID: 14973102, 26689913, 30039884, 30078507, 30093976). ClinVar contains an entry for this variant (Variation ID: 51246). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000130632	SCV000185508	likely benign	Hereditary cancer-predisposing syndrome	2022-09-06	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	RCV000216194	SCV000279893	uncertain significance	not provided	2023-08-28	criteria provided, single submitter	clinical testing	Observed in individuals with BRCA2-related cancers but also in healthy controls (Suter et al., 2004; Lu et al., 2015; Li et al., 2018; Dong et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 2350T>A; This variant is associated with the following publications: (PMID: 14973102, 30078507, 10923033, 28774860, 26689913, 32467295, 31825140, 31131967, 30093976)
Counsyl	RCV000113017	SCV000785073	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-03-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763881	SCV000894816	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130632	SCV000903950	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 708 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 been reported in individuals affected with breast, ovarian and colorectal cancer and in similar number of unaffected individuals (PMID: 14973102, 26689913, 27157322, 30078507, 30093976, 33471991; Leiden Open Variation Database DB-ID BRCA2_007135). This variant has been identified in 7/282362 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	RCV001194412	SCV001363948	uncertain significance	not specified	2023-09-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2122T>A (p.Ser708Thr) 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 5.9e-05 in 305134 control chromosomes (gnomAD, Dong_2021). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (5.9e-05 vs 0.00075), allowing no conclusion about variant significance. c.2122T>A has been reported in the literature in individuals affected with Colon Cancer (Chan_2018) and Breast and/or Ovarian Cancer (e.g. Dong_2018, Kwong_2016, Li_2018, Suter_2004, Lu_2015, Guo_2020, Dorling_2021, Feng_2023). These reports do 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. The following publications have been ascertained in the context of this evaluation (PMID: 30093976, 30039884, 27157322, 30078507, 26689913, 14973102, 32467295, 37116400, 31837001, 33471991). Seven ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130632	SCV003846511	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).
All of Us Research Program, National Institutes of Health	RCV000113017	SCV004847008	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 708 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 been reported in individuals affected with breast, ovarian and colorectal cancer and in similar number of unaffected individuals (PMID: 14973102, 26689913, 27157322, 30078507, 30093976, 33471991; Leiden Open Variation Database DB-ID BRCA2_007135). This variant has been identified in 7/282362 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001194412	SCV005090021	benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000113017	SCV005405002	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-08-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113017	SCV000146008	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-07-07	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735530	SCV000863668	uncertain significance	Breast and/or ovarian cancer	2001-05-08	no assertion criteria provided	clinical testing