rs937218360
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000251.3(MSH2):c.1294T>A(p.Leu432Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L432F) has been classified as Likely benign.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1294T>A | p.Leu432Met | missense_variant | 8/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1294T>A | p.Leu432Met | missense_variant | 8/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459644Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 726226
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Lynch syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate mismatch repair function more likely to be neutral (Jia et al., 2020); This variant is associated with the following publications: (PMID: 18822302, 21120944, 33357406) - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 25, 2023 | 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 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 not expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 663232). 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 leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 432 of the MSH2 protein (p.Leu432Met). - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at