ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.512G>A (p.Arg171Lys) (rs63750902)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000627693 SCV000548143 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-09-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 171 of the MSH2 protein (p.Arg171Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs63750902, ExAC 0.05%). This variant has been reported in the literature in an individual affected with early-onset rectal cancer (PMID: 15345113). ClinVar contains an entry for this variant (Variation ID: 91119). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). The lysine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In addition, an algorithm developed specifically for the MSH2 suggests that this variant is likely to be tolerated (PMID: 18383312). These predictions have not been confirmed by published functional studies. 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 RCV000570883 SCV000662292 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-23 criteria provided, single submitter clinical testing The p.R171K variant (also known as c.512G>A), located in coding exon 3 of the MSH2 gene, results from a G to A substitution at nucleotide position 512. The arginine at codon 171 is replaced by lysine, an amino acid with highly similar properties. This alteration was seen once in a cohort of 12 MSI-H colon cancer patients of Indian descent and was reported as a variant of unknown significance (Rajkumar T et al., Genet. Test. 2004 ; 8(2):157-62). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000570883 SCV000911207 likely benign Hereditary cancer-predisposing syndrome 2016-03-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001137124 SCV001297032 uncertain significance Lynch syndrome I 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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