ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.766G>A (p.Ala256Thr) (rs377403073)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160627 SCV000211226 uncertain significance not provided 2020-06-02 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with ovarian and renal cancer (Pal 2012, Yehia 2018); This variant is associated with the following publications: (PMID: 23047549, 29684080)
Invitae RCV000196535 SCV000254429 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 256 of the MSH2 protein (p.Ala256Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs377403073, ExAC 0.06%). This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 182590). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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 RCV000491536 SCV000580572 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-02 criteria provided, single submitter clinical testing The p.A256T variant (also known as c.766G>A), located in coding exon 4 of the MSH2 gene, results from a G to A substitution at nucleotide position 766. The alanine at codon 256 is replaced by threonine, an amino acid with similar properties. This alteration was detected in a cohort of 1893 women with epithelial ovarian cancer from three population-based studies who were ascertained for mutations in MLH1, MSH2 and MSH6 (Pal T et al. Br. J. Cancer. 2012 Nov;107:1783-90). This alteration has been observed in one individual from a cohort of patients with Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations (Yehia L et al. PLoS Genet. 2018 04;14:e1007352). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000662661 SCV000785350 uncertain significance Lynch syndrome I 2017-07-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160627 SCV000888231 uncertain significance not provided 2019-01-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000491536 SCV000911380 likely benign Hereditary cancer-predisposing syndrome 2016-01-07 criteria provided, single submitter clinical testing

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