ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1915C>T (p.His639Tyr) (rs28929484)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000030246 SCV000107343 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration (full inactivation variant allele)
Ambry Genetics RCV000491611 SCV000580461 pathogenic Hereditary cancer-predisposing syndrome 2019-01-09 criteria provided, single submitter clinical testing Result Def in combination with c.2211-1G>T: The c.1915C>T alteration (also known as p.H639Y), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1915. The histidine at codon 639 is replaced by tyrosine, an amino acid with similar properties. The c.2211-1G>T intronic alteration, results from a G to T one nucleotide upstream from coding exon 14 of the MSH2 gene. In one study, c.2211-1G>T was detected in cis with c.1915C>T, and this complex double mutation caused an in frame deletion of exons 12-14 in a patient diagnosed with colon cancer before 30 years of age. This result also correlated with short fragments detected by in vitro synthesized-protein–truncation assay. This individual's cancer was noted to exhibit microsatellite instability on tumor studies (Farrington et al. Am J Hum Genet. 1998 Sep; 63(3): 749-59). Based on the available evidence, the c.1915C>T+ c.2211-1G>T haplotype is interpreted as a disease-causing. Result Def when seen alone: The c.1915C>T pathogenic mutation (also known as p.H639Y), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1915. The histidine at codon 639 is replaced by tyrosine, an amino acid with similar properties. In one study, c.1915C>T was detected in a HNPCC kindred and it was predicted to create a novel donor splice site and to cause out of frame deletion of codons 638-669 creating a new termination codon 17 bp downstream of the splice site (Liu et al. Cancer Res. 1994 Sep 1; 54(17): 4590-4). mRNA analysis of this alteration confirmed an aberrant splicing with deletion of 92 bases between 1914 and 2005 (r.1914_2005del) (Auclair et al. Hum Mut .2006 Feb; 27(2): 145-54). Yet in another study, c.1915C>T was detected in cis with another splicing mutation, c.2211-1G>T, and this double mutation caused deletion of exons 12-14 in a young patient diagnosed with colon cancer less than 30 years of age. This result also correlated with short fragments detected by in vitro synthesized-protein–truncation assay (Farrington et al. Am J Hum Genet. 1998 Sep; 63(3): 749-59). Based on the available evidence to date, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001204094 SCV001375285 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-07-07 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 639 of the MSH2 protein (p.His639Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with clinical features of hereditary non-polyposis colorectal cancer (PMID: 8062247, 8261515, 11555625, 16395668, 9718327, 11920458). ClinVar contains an entry for this variant (Variation ID: 1756). This variant has been reported to affect MSH2 protein function (PMID: 17720936). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16395668, 8062247). 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.
OMIM RCV000001826 SCV000021982 pathogenic Lynch syndrome I 1993-12-17 no assertion criteria provided literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030246 SCV000052913 likely pathogenic Lynch syndrome 2015-10-02 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202104 SCV000257159 pathogenic not provided no assertion criteria provided clinical testing

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