rs587781447
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PM2PP3_ModerateBP6
The NM_000251.3(MSH2):c.260C>A(p.Ser87Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,611,528 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S87C) has been classified as Likely benign.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000661 AC: 1AN: 151214Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.00000797 AC: 2AN: 250910 AF XY: 0.00000737 show subpopulations
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460314Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726470 show subpopulations
GnomAD4 genome AF: 0.00000661 AC: 1AN: 151214Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 73748 show subpopulations
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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. -
This missense variant replaces serine with tyrosine at codon 87 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/250910 chromosomes 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. -
Lynch syndrome 1 Uncertain:1
The MSH2 c.260C>A (p.Ser87Tyr) missense change has a maximum subpopulation frequency 0.0054% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/2-47635588-C-A). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in individuals with breast cancer (PMID: 32547938) and one individual with relapsed pediatric T-lymphoblastic leukemia (PMID: 32547938). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, PP3. -
Lynch syndrome Uncertain:1
This missense variant replaces serine with tyrosine at codon 87 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/250910 chromosomes 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:1
This variant is denoted MSH2 c.260C>A at the cDNA level, p.Ser87Tyr (S87Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCT>TAT). This variant was not observed in a cohort of individuals diagnosed with colon cancer, however it was identified in an unaffected control (Arora 2015). MSH2 Ser87Tyr was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Tyrosine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Ser87Tyr occurs at a position that is conserved in mammals and is located in the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Ser87Tyr is a pathogenic variant or a benign variant. We consider it to be a variant of uncertain significance. -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at