Submissions for variant NM_000059.4(BRCA2):c.7507G>A (p.Val2503Ile)

gnomAD frequency: 0.00002  dbSNP: rs587782191

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130837	SCV000185735	likely benign	Hereditary cancer-predisposing syndrome	2019-02-15	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.
Invitae	RCV000459125	SCV000549651	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2503 of the BRCA2 protein (p.Val2503Ile). This variant is present in population databases (rs587782191, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, pancreatic cancer, and/or familial non-medullary thyroid cancer (PMID: 22034289, 25802882, 26530882, 27741520, 29088781, 30287823, 32980694). ClinVar contains an entry for this variant (Variation ID: 142036). 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.
GeneDx	RCV000479926	SCV000565719	uncertain significance	not provided	2019-09-23	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history including breast, pancreatic, and other cancers (Fackenthal 2012, Hirotsu 2015, Yu 2015, Fernandes 2016, Alvarez 2017, Kondo 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 7735G>A; This variant is associated with the following publications: (PMID: 22034289, 25802882, 26530882, 27741520, 28422758, 29088781, 29731985)
Counsyl	RCV000662953	SCV000785919	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130837	SCV000911414	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2503 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 and/or ovarian cancer (PMID: 22034289, 25802882, 27741520, 29088781), an individual affected with familial non-medullary thyroid cancer (PMID: 26530882), and in an individual affected with bile duct cancer (PMID: 31666926). This variant has also been detected in breast, pancreatic and prostate case-controls studies in the Japanese population and found in both cohorts, in which disease association could not be established (PMID: 30287823, 31214711, 32980694). This variant has been identified in 1/251416 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	RCV000779919	SCV000916845	uncertain significance	not specified	2018-02-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7507G>A (p.Val2503Ile) results in a conservative amino acid change located in the helical domain (IPR015252, InterPro), that belongs to the BRCA2 DNA-binding domain. 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 4.1e-06 in 246186 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.7507G>A variant has been reported in the literature in individuals affected with HBOC and non-medullary thyroid cancer (Hirotsu 2014, Fackenthal 2012, Fernandes 2016, Alvarez 2017), however these report(s) do not provide unequivocal conclusions about association of the variant with HBOC. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479926	SCV002046166	uncertain significance	not provided	2021-04-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000779919	SCV002517988	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130837	SCV002531865	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-03	criteria provided, single submitter	curation
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000662953	SCV003807103	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-02-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 supporting, BP4 supporting
PreventionGenetics, part of Exact Sciences	RCV004528856	SCV004104739	uncertain significance	BRCA2-related disorder	2023-07-19	criteria provided, single submitter	clinical testing	The BRCA2 c.7507G>A variant is predicted to result in the amino acid substitution p.Val2503Ile. This variant has been reported in patients with breast cancer and non-medullary thyroid cancer and interpreted as uncertain in multiple reports (Table S1, Alvarez et al 2017. PubMed ID: 29088781; Fernandes et al 2016. PubMed ID: 27741520; Table S1, Dong et al. 2021. PubMed ID: 32467295; Hirotsu et al. 2015. PubMed ID: 25802882; Fackenthal et al. 2012. PubMed ID: 22034289; Yu et al. 2015. PubMed ID: 26530882). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32930636-G-A); and, it is listed with conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142036/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000662953	SCV004844420	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2503 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 and/or ovarian cancer (PMID: 22034289, 25802882, 27741520, 29088781), an individual affected with familial non-medullary thyroid cancer (PMID: 26530882), and in an individual affected with bile duct cancer (PMID: 31666926). This variant has also been detected in breast, pancreatic and prostate case-controls studies in the Japanese population and found in both cohorts, in which disease association could not be established (PMID: 30287823, 31214711, 32980694). This variant has been identified in 1/251416 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000479926	SCV001743305	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000479926	SCV001906344	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000479926	SCV001955724	likely benign	not provided		no assertion criteria provided	clinical testing