Submissions for variant NM_000251.3(MSH2):c.215C>G (p.Ala72Gly)

dbSNP: rs1558457009

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689690	SCV000817353	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-24	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 72 of the MSH2 protein (p.Ala72Gly). ClinVar contains an entry for this variant (Variation ID: 569135). 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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 333574060) indicates that this missense variant is not expected to disrupt MSH2 function.
Ambry Genetics	RCV001014484	SCV001175198	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-28	criteria provided, single submitter	clinical testing	The p.A72G variant (also known as c.215C>G), located in coding exon 2 of the MSH2 gene, results from a C to G substitution at nucleotide position 215. The alanine at codon 72 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 Diagnostics, LLC DBA Color Health	RCV001014484	SCV001340677	uncertain significance	Hereditary cancer-predisposing syndrome	2019-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193287	SCV001362022	uncertain significance	not specified	2019-05-17	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.215C>G (p.Ala72Gly) results in a non-conservative amino acid change located in the N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250342 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.215C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004788122	SCV005402194	uncertain significance	Lynch syndrome 1	2024-04-24	criteria provided, single submitter	clinical testing	The MSH2 c.215C>G (p.Ala72Gly) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.?