Submissions for variant NM_000251.3(MSH2):c.1915C>T (p.His639Tyr)

dbSNP: rs28929484

Total submissions: 9

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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987305	SCV000052913	pathogenic	Hereditary nonpolyposis colon cancer	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1915C>T (p.His639Tyr) results in a conservative amino acid change located in the DNA mismatch repair protein Msh2, ATP-binding cassette domain (IPR032642) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 5' donor site. One predicts the variant strengthens a cryptic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (example: Auclair_2006). The variant was absent in 251510 control chromosomes (gnomAD). c.1915C>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (example: Liu_1994, Leach_1993, Farrington_MSH2_AJHG_1998, Furukawa_2002, Auclair_2006, Terui_2013). At-least one of these reports have published a pathogenic variant in cis in one of the affected individuals (Farrington_1998). Multiple reports have published experimental evidence evaluating an impact on protein function. One of these studies showed the variant causes a defect in MMR function by in vivo drug-resistance assay in yeast; impair subunit interaction with Msh6 or Msh3, and reduce normal protein expression (example: Gammie_2007). The following publications have been ascertained in the context of this evaluation (PMID: 11555625, 9718327, 18383312, 8062247, 16395668, 14518068, 8261515, 9630599, 17720936, 17192056, 19339519, 22290698, 25559809, 11920458, 24100870). ClinVar contains an entry for this variant (Variation ID: 1756). Based on the evidence outlined above, the variant was classified as pathogenic.
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. This variant has been identified in probands whose family histories met Amsterdam I/II criteria for Lynch syndrome and one was diagnosed with uterine cancer that demonstrated loss of both MSH2/MSH6 expression by immunohistochemistry (Ambry internal data). 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 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). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001204094	SCV001375285	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-06-09	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 639 of the MSH2 protein (p.His639Tyr). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 8062247, 16395668). Experimental studies have shown that this missense change affects MSH2 function (PMID: 17720936). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 1756). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 8062247, 8261515, 9718327, 11555625, 11920458, 16395668; Invitae).
Revvity Omics, Revvity	RCV000202104	SCV002017560	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000001826	SCV004187918	pathogenic	Lynch syndrome 1	2023-08-04	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 8062247, 16395668].
All of Us Research Program, National Institutes of Health	RCV000030246	SCV004829863	pathogenic	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 639 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools indicate that this variant may activate a cryptic splice donor site 90 nucleotides upstream of the native intron 13 splice donor site. Functional RNA studies have shown that this cryptic splice donor site is used, leading to a deletion of 92 nucleotides in exon 12 (PMID: 8062247, 11920458, 16395668, 31588121, 32849802). As a result, this variant creates a frameshift and premature translation stop signal and is expected to result in an absent or non-functional protein product. This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). Other studies reported that the variant retained at least 58% of wild type MSH2 mismatch repair activity via mismatch repair assays in yeast (PMID: 11555625, 17720936). This variant has been reported in individuals affected with Lynch syndrome and colorectal cancer (PMID: 8062247, 8261515, 9718327, 11920458, 16395668, 24100870, 27329137, 31197828, 31588121). Some of these individuals also carried a pathogenic c.2211-1G>T in cis with this variant in MSH2 gene that could explain the observed phenotype (PMID: 9718327, 27329137). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
OMIM	RCV000001826	SCV000021982	pathogenic	Lynch syndrome 1	1993-12-17	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000202104	SCV000257159	pathogenic	not provided		no assertion criteria provided	clinical testing