Submissions for variant NM_000059.4(BRCA2):c.572A>G (p.Asp191Gly)

dbSNP: rs397507798

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV003162382	SCV003853788	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-17	criteria provided, single submitter	clinical testing	The c.572A>G variant (also known as p.D191G), located in coding exon 6 of the BRCA2 gene, results from an A to G substitution at nucleotide position 572. RNA studies have demonstrated that this alteration results in abnormal splicing that results in the in-frame loss of 20 amino acids (Ambry internal data; Gaildrat P et al. J Med Genet, 2012 Oct;49:609-17; Fraile-Bethencourt E et al. J Pathol, 2019 Aug;248:409-420); however, the exact functional impact of the deleted amino acids is unknown at this time. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017342	SCV004847903	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Asp191Gly variant in BRCA2 has been reported in 2 individuals with early-onset breast cancer (Gaildrat 2012). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Asp191Gly variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, in vitro splicing assays provide evidence that this variant leads to a splicing change, resulting in the in-frame deletion of 20 amino acids (Gaildrat 2012, Fraile-Bethencourt 2019); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP3, PS4_Supporting.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577576	SCV000678771	not provided	Familial cancer of breast		no assertion provided	literature only