rs63750379
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000251.3(MSH2):āc.1223A>Gā(p.Tyr408Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y408F) has been classified as Likely benign.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1223A>G | p.Tyr408Cys | missense_variant | 7/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1223A>G | p.Tyr408Cys | missense_variant | 7/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461810Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727218
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74326
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 11, 2023 | The p.Y408C variant (also known as c.1223A>G), located in coding exon 7 of the MSH2 gene, results from an A to G substitution at nucleotide position 1223. The tyrosine at codon 408 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in an individual with sporadic gastric cancer (Fan Y et al. Cancer Genet Cytogenet. 2006 Oct 15;170(2):121-8). Structural modeling suggests that this alteration disrupts ionic interaction with a neighboring residue; however, direct experimental evidence of pathogenicity was not available (Ali H et al. Hum. Mutat. 2012 Apr;33(4):642-50.) Yeast-two hybridization assay demonstrated plasmids with this alteration have slow growth compared to wild type, indicating that this alteration partially affects the function of hMSH2 (Zhang X et al. Oncol Lett. 2018 May;15:6275-6282). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). In addition, a study of the functional significance of MSH2 missense variants using CRISPR-Cas9 gene editing in human embryonic stem cells suggests this alteration is proficient at DNA repair function, damage response signaling and protein stability (Rath A et al. Hum Mutat, 2019 Nov;40:2044-2056). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 09, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 24, 2023 | This missense variant replaces tyrosine with cysteine at codon 408 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). 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). In another functional study, this variant had no impact on protein stability, DNA damage response signaling, or DNA repair function (PMID: 31237724). This variant has been reported in an individual affected with gastric cancer (PMID: 16929514, 17011982). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 0/53461 unaffected controls (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 20, 2017 | Variant summary: The MSH2 c.1223A>G (p.Tyr408Cys) variant located in the DNA mismatch repair protein MutS, core domain (via InterPro) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome. However, publications provide conflicting information as to whether the missense change will affect protein function: Ali_2012 indicates the variant plays a key role in the ionic interaction with E455 in another alpha-helix is removed, while Fan_2006 indicates "both tyrosine and cysteine are uncharged amino acids, and this region is not conserved and according to structure modeling, the substitution of tyrosine and cysteine makes no difference in the H-bonds." This variant is absent in 121524 control chromosomes (ExAC and publication controls). A publication, Fan_2006, cites the variant to have been found in a sporadic gastric cancer pt, although with limited information (lack of co-occurrence and cosegregation data). A functional yeast study presented in Chinese indicates in the translated abstract that the variant of interest grew slower and could affect MSH2 function, however, additional studies need to be performed to support this finding. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18383312, 22290698, 23760103, 16929514, 17011982, 24078570, 33471991, 31237724, 33357406, 29731845, 18822302, 21120944) - |
Lynch syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 09, 2023 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces tyrosine with cysteine at codon 408 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). 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). In another functional study, this variant had no impact on protein stability, DNA damage response signaling, or DNA repair function (PMID: 31237724). This variant has been reported in an individual affected with gastric cancer (PMID: 16929514, 17011982). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 0/53461 unaffected controls (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 408 of the MSH2 protein (p.Tyr408Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with gastric cancer (PMID: 16929514). ClinVar contains an entry for this variant (Variation ID: 90574). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MSH2 function (PMID: 29731845, 33357406). 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. - |
Mismatch repair cancer syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 10, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at