Submissions for variant NM_000059.4(BRCA2):c.7691C>G (p.Thr2564Ser)

gnomAD frequency: 0.00001  dbSNP: rs431825355

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483608	SCV000565929	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing	Observed in individuals with breast or ovarian cancer, and in unaffected controls (Park et al., 2016; So et al., 2019; Guo et al., 2020; Kim et al., 2020; Dorling et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7919C>G; This variant is associated with the following publications: (PMID: 12228710, 30725392, 29884841, 32467295, 32377563, 33471991, 31837001, 31907386, 32566972, 27124784)
Ambry Genetics	RCV000575205	SCV000666116	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-26	criteria provided, single submitter	clinical testing	The p.T2564S variant (also known as c.7691C>G), located in coding exon 15 of the BRCA2 gene, results from a C to G substitution at nucleotide position 7691. The threonine at codon 2564 is replaced by serine, an amino acid with similar properties. This alteration was identified in two individuals from a cohort of 715 Korean breast cancer patients and classified as likely benign using ACMG's standards for variant classification based population data, computational data, functional data, clinical phenotype and segregation information (Park KS et al. Genet. Med., 2016 12;18:1250-1257). In a case control study, this variant was reported in 4/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). The alteration has also been described in other individuals diagnosed with breast and/or ovarian cancer (So MK et al. Breast Cancer, 2019 Jul;26:510-519, Kim HK et al. J Hum Genet, 2020 Mar;65:209-220), but also in unaffected controls (Dong H et al. J Med Genet, 2021 08;58:565-569). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806708	SCV000946722	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 2564 of the BRCA2 protein (p.Thr2564Ser). This variant is present in population databases (rs431825355, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 27124784, 31837001, 31907386). ClinVar contains an entry for this variant (Variation ID: 418684). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483608	SCV004220569	uncertain significance	not provided	2023-08-21	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast/ovarian cancer (PMIDs: 31907386 (2020), 31837001 (2020), 30725392 (2019), 30287823 (2018), 27124784 (2016)), and in unaffected control individuals (PMIDs: 32467295 (2020), 33471991 (2021)). This variant has also been described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.00016 (3/18392 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	RCV004802049	SCV005425761	uncertain significance	BRCA2-related cancer predisposition	2024-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 2564 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 cancer (PMID: 27124784, 33471991). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 4/60466 cases and 2/53461 unaffected controls, showing inconclusive association with disease (OR=1.768 (95%CI 0.324 to 9.655); p-value=0.691; Leiden Open Variation Database DB-ID BRCA2_008617) (PMID: 33471991). This variant has been identified in 3/251304 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000806708	SCV005688937	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-15	criteria provided, single submitter	clinical testing	The missense variant NM_000059.4(BRCA2):c.7691C>G (p.Thr2564Ser) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. There is a small physicochemical difference between threonine and serine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene BRCA2 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.00. The p.Thr2564Ser missense variant is predicted to be tolerated by both SIFT or PolyPhen2. For these reasons, this variant has been classified as Uncertain Significance