Submissions for variant NM_000059.4(BRCA2):c.572A>T (p.Asp191Val)

dbSNP: rs397507798

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129294	SCV000184055	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-04	criteria provided, single submitter	clinical testing	The p.D191V variant (also known as c.572A>T), located in coding exon 6 of the BRCA2 gene, results from an A to T substitution at nucleotide position 572. The aspartic acid at codon 191 is replaced by valine, an amino acid with highly dissimilar properties. In one functional study, this variant was observed to result in a threefold increase in homologous recombination compared to wild type (p<0.0001) (Balia C et al. Breast Cancer Res. Treat. 2011;129(3):1001-9). One mini-gene splicing assay indicated that the c.572A>T alteration resulted in a slight increase in the percentage of transcripts with exon 7 skipping compared to wild type (Di Giacomo D et al. Hum. Mutat. 2013 Nov;34(11):1547-57). This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Rizzolo P et al. Int J Cancer, 2019 Jul;145:390-400; Fu K et al. Sci Rep, 2024 Mar;14:6702). Of note, this alteration is also designated as 800A>T in published literature. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Counsyl	RCV000411982	SCV000487785	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000486563	SCV000568449	uncertain significance	not provided	2016-09-28	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.572A>T at the cDNA level, p.Asp191Val (D191V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). This variant, previously published as BRCA2 800A>T, was identified in at least two individuals with a personal and/or family history of breast cancer (Balia 2011). Balia et al. (2011) showed that this variant lead to an increased rate of homologous recombination, when compared to wild-type; however, tumor analysis revealed no loss of heterozygosity. While skipping of BRCA2 exon 7 is a naturally occurring isoform, BRCA2 Asp191Val has been shown to mildly increase this exon skipping compared to wild-type (Di Giacomo 2013). BRCA2 Asp191Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp191Val occurs at a position where amino acids with properties similar to Aspartic Acid are tolerated across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Asp191Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129294	SCV001347757	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 191 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). RNA studies using minigene splicing assay reported that this variant caused low-level of exon skipping (PMID: 23983145, 26761715). This variant has been reported in three individuals affected with breast cancer and at least one additional suspected hereditary breast and ovarian cancer family and an unaffected individual (PMID: 21671020, 33471991; Leiden Open Variation Database DB-ID BRCA2_000499, 35115620). This variant also has been observed in an individual affected with lung cancer (PMID: 31721094). This variant has been identified in 1/251414 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001373010	SCV001569708	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 191 of the BRCA2 protein (p.Asp191Val). This variant is present in population databases (rs397507798, gnomAD 0.006%). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer or squamous cell carcinoma (PMID: 21671020, 30613976). ClinVar contains an entry for this variant (Variation ID: 51921). 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%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 21671020). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153337	SCV003843748	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000411982	SCV004228298	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting)+BP1(Strong)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)