rs63751598
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000249.4(MLH1):c.883A>C(p.Ser295Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/25 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S295G) has been classified as Pathogenic.
Frequency
Consequence
NM_000249.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.883A>C | p.Ser295Arg | missense_variant, splice_region_variant | 10/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.883A>C | p.Ser295Arg | missense_variant, splice_region_variant | 10/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 13, 2021 | This missense variant replaces a serine with an arginine in codon 295 of the MLH1 gene. Functional RNA studies have shown that this variant results in exon 10 skipping (PMID: 16830052, 26761715), predicted to lead to a frameshift and premature translation stop signal. This is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 18618713, http://www.insight-database.org) or colorectal cancer (PMID: 16830052). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 08, 2024 | The c.883A>C variant (also known as p.S295R), located in coding exon 10 of the MLH1 gene, results from an A to C substitution at nucleotide position 883. The serine at codon 295 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported in an individual with MSI-H, MLH1-absent colorectal cancer diagnosed at age 32, whose family met Amsterdam II criteria (Alemayehu A et al. Genes Chromosomes Cancer, 2008 Oct;47:906-14). RT-PCR and minigene assays indicate that this alteration leads to the skipping of exon 10 and a subsequent frameshift (Kurzawski G et al. Clin Genet, 2006 Jan;69:40-7; Zavodna K et al. Neoplasma, 2006;53:269-76); Soukarieh O et al. PLoS Genet, 2016 Jan;12:e1005756). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Carcinoma of colon Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Ser295Arg variant has been reported in the literature in 3 out of 652 proband chromsomes in individuals who met Amsterdam and Bethesda criteria for HNPCC and was not identified in 60 control chromosomes from these studies (Kurzawski 2006, Alemayehu 2008, Bujalkova 2008). In addition, this variant has been previously reported by our laboratory in two families with a strong family history of colon and endometrial cancer. In one individual tested, a tumor was MSI-H and deficient for MLH1 by immunohistochemistry suggesting absent protein product and a functional consequence of this variant. Furthermore, another variant at the same position (c.883A>G, p.Ser295Gly) has been identified by our laboratory in one family and met our criteria for pathogenicity, increasing the likelihood that this variant also has clinical significance. The p.Ser295Arg variant occurs in the second last base of the exon and this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing further supporting a pathogenic role for this variant. In summary, based on the above information this variant is classified as Pathogenic. - |
Lynch syndrome Pathogenic:1
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Variant allele results in splicing abberation leading to premature stop codon: full inactivation of variant allele - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 06, 2022 | For these reasons, this variant has been classified as Pathogenic. Other variant(s) that result in skipping of exon 10 have been determined to be pathogenic (PMID: 15713769, 15849752, 26247049, 26761715; Invitae). This suggests that this variant may also be clinically significant and likely to be disease-causing. Studies have shown that this missense change is associated with altered splicing resulting in exon 10 skipping and introducing a premature termination codon (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 90408). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 16451135, 16830052, 18618713, 18772310, 20223024). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 295 of the MLH1 protein (p.Ser295Arg). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at