2-47463124-T-C
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6
The NM_000251.3(MSH2):c.1480T>C(p.Ser494Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S494S) has been classified as Benign.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
Publications
- Lynch syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
- Lynch syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
- Muir-Torre syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
- mismatch repair cancer syndrome 1Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- mismatch repair cancer syndrome 2Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- ovarian cancerInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- malignant pancreatic neoplasmInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- rhabdomyosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- breast cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
- hereditary breast carcinomaInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000279 AC: 7AN: 251294 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461702Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727156 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152274Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74444 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
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This alteration is classified as 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. -
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Lynch syndrome 1 Uncertain:1
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not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest no impact on mismatch repair function (Jia et al., 2020); Observed in individuals with breast cancer, colon cancer, and/or polyps (Yurgelun et al., 2015; Chang et al., 2016; Chen et al., 2020); This variant is associated with the following publications: (PMID: 26900293, 25980754, 18822302, 9774676, 21120944, 33357406, 32091409) -
Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Uncertain:1
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Lynch syndrome Benign:1
This missense variant replaces serine with proline at codon 494 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual each affected with colorectal cancer (PMID: 26900293) and Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754), in the latter case the individual also had a pathogenic BRCA1 structural variant. This variant has been identified in 8/282692 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. -
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