Submissions for variant NM_000059.4(BRCA2):c.5231G>T (p.Ser1744Ile)

gnomAD frequency: 0.00001  dbSNP: rs587782060

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130537	SCV000185406	likely benign	Hereditary cancer-predisposing syndrome	2022-08-04	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198995	SCV000254190	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1744 of the BRCA2 protein (p.Ser1744Ile). This variant is present in population databases (rs587782060, gnomAD 0.04%). This missense change has been observed in individual(s) with breast, ovarian cancer and colorectal cancer (PMID: 27907908, 28664449, 32548945). ClinVar contains an entry for this variant (Variation ID: 141853). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Counsyl	RCV000410002	SCV000488107	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590786	SCV000694847	uncertain significance	not specified	2020-07-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5231G>T (p.Ser1744Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249282 control chromosomes, exclusively within the East Asian subpopulation in the gnomAD database at a frequency of 0.00033. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5231G>T has been reported in the literature in individuals affected with breast cancer (e.g. Li_2017, Tria_2019), ovarian cancer (e.g. Chao_2016), Lynch Syndrome (e.g. Xu_2020), and DLBCL (e.g. deMiranda_2013). These publications do not report strong evidence for causality and thus 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. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130537	SCV000906104	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 1744 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 lymphoma, breast, ovarian, and colorectal cancer (PMID: 23960188, 27907908, 28664449, 32548945). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 6/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007158). This variant has been identified in 7/280688 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284091	SCV001469691	uncertain significance	not provided	2019-11-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505110	SCV002782687	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	2021-08-25	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130537	SCV003847099	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).
Myriad Genetics, Inc.	RCV000410002	SCV004019719	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-04-03	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].
All of Us Research Program, National Institutes of Health	RCV000410002	SCV004845789	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 1744 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 lymphoma, breast, ovarian, and colorectal cancer (PMID: 23960188, 27907908, 28664449, 32548945). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 6/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007158). This variant has been identified in 7/280688 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.