Submissions for variant NM_000059.4(BRCA2):c.8254A>T (p.Ile2752Phe)

dbSNP: rs80359072

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045463	SCV000073476	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2752 of the BRCA2 protein (p.Ile2752Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 21232165, 22366370). ClinVar contains an entry for this variant (Variation ID: 52538). 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.
Ambry Genetics	RCV000130435	SCV000185299	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	The p.I2752F variant (also known as c.8254A>T), located in coding exon 17 of the BRCA2 gene, results from an A to T substitution at nucleotide position 8254. The isoleucine at codon 2752 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in Slovenian and Croatian breast and/or ovarian cancer families (Stegel V et al. BMC Med Genet. 2011 Jan 14;12:9; Levanat S et al. Gene. 2012 May 1;498(2):169-76). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000130435	SCV001340338	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with phenylalanine at codon 2752 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 2/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000302) and in suspected hereditary breast and ovarian cancer families (PMID: 21232165, 22366370). A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 0.3348, respectively (PMID: 31131967). This variant has not been identified 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.
GeneDx	RCV001582544	SCV001811966	likely benign	not provided	2021-02-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31131967, 22366370, 19043619, 21232165)
All of Us Research Program, National Institutes of Health	RCV000113898	SCV004845626	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with phenylalanine at codon 2752 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 2/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000302) and in suspected hereditary breast and ovarian cancer families (PMID: 21232165, 22366370). A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 0.3348, respectively (PMID: 31131967). This variant has not been identified 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	RCV001582544	SCV005625313	uncertain significance	not provided	2024-07-30	criteria provided, single submitter	clinical testing	The BRCA2 c.8254A>T (p.Ile2752Phe) variant has been reported in the published literature in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 38785549 (2024), 22366370 (2012), 21232165 (2011)). This variant was reported as being likely benign in a multifactorial likelihood study (PMID: 31131967 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113898	SCV000147313	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing