Submissions for variant NM_000059.4(BRCA2):c.518G>T (p.Gly173Val)

gnomAD frequency: 0.00001  dbSNP: rs28897702

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044598	SCV000072611	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 173 of the BRCA2 protein (p.Gly173Val). This variant is present in population databases (rs28897702, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 25682074, 28205045). ClinVar contains an entry for this variant (Variation ID: 51810). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 21671020). 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	RCV000213680	SCV000273887	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-07	criteria provided, single submitter	clinical testing	The p.G173V variant (also known as c.518G>T), located in coding exon 6 of the BRCA2 gene, results from a G to T substitution at nucleotide position 518. The glycine at codon 173 is replaced by valine, an amino acid with dissimilar properties. This alteration was identified in a cohort of high-risk breast and ovarian cancer patients (Park B et al. Breast Cancer Res. Treat., 2017 May;163:139-150). A functional assay shows that this alteration behaved like wildtype in a spontaneous homologous repair assay, however, the assay was not robust enough to predict clinical relevance of tested variants (Balia C et al. Breast Cancer Res. Treat., 2011 Oct;129:1001-9). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however, the literature harbors conflicting results in terms of the generation of abnormal transcripts from a splicing minigene assay with one paper reporting exon 7 skipping as a minor isoform while another reports no abnormal transcripts (Sanz DJ et al. Clin. Cancer Res., 2010 Mar;16:1957-67; Di Giacomo D et al. Hum. Mutat., 2013 Nov;34:1547-57). This amino acid position is conserved on limited sequence alignment. 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.
Color Diagnostics, LLC DBA Color Health	RCV000213680	SCV001735484	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 173 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). Functional RNA studies using minigene splicing assays reported conflicted findings of a partial splicing defect and no detectable defect (PMID: 20215541, 23983145). This variant has been reported in an individual with suspected hereditary breast cancer (PMID: 28205045) and another individual affected with triple-negative breast cancer (PMID: 25682074). This variant has been identified in 3/251340 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004595903	SCV005090011	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113738	SCV000147058	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing