ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.517G>T (p.Gly173Cys) (rs397507768)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220016 SCV000273700 uncertain significance Hereditary cancer-predisposing syndrome 2015-01-30 criteria provided, single submitter clinical testing The p.G173C variant (also known as c.517G>T and 745G>T) located in coding exon 6 of the BRCA2 gene. The glycine at codon 173 is replaced by cysteine, an amino acid with highly dissimilar properties. This change occurs in the first base pair of exon 7 which makes it likely to have some effect on normal mRNA splicing. A mini-gene assayprovidesin vitroevidence indicating c.517G>T results in complete skipping ofexon 7 in the mini-gene; however,in vivofunctional analysis is not available at this time(Gaildrat Pet al.J. Med. Genet. 2012 Oct; 49(10):609-17).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 105,000alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native acceptor splice site; however, direct in vivo evidence is unavailable. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.G173C remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506327 SCV000600629 uncertain significance not specified 2016-12-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000220016 SCV000683683 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-05 criteria provided, single submitter clinical testing This missense variant replaces glycine with cysteine at codon 173 of the BRCA2 protein. RNA studies using the mini-gene assay have reported that this variant affects RNA splicing and results in exon 7 skipping and protein truncation (PMID: 22962691, 30883759). A different variant occurring at the same nucleotide position, c.517G>C, has been shown to affect RNA splicing in cells derived from a carrier individual (PMID: 29280214), indicating that a change to the c.G nucleotide at this position impacts RNA splicing. This variant has been reported in multiple individuals affected with familial breast cancer (PMID: 22962691, 25777348, 27463008, 28947987; Color internal data; UMD database). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV001301980 SCV001491167 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 173 of the BRCA2 protein (p.Gly173Cys). The glycine residue is weakly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 22962691, 28947987, 25777348). ClinVar contains an entry for this variant (Variation ID: 51805). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 30883759). 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.
Sharing Clinical Reports Project (SCRP) RCV000239003 SCV000297536 uncertain significance Breast-ovarian cancer, familial 2 2013-02-26 no assertion criteria provided clinical testing

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