ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.739T>C (p.Ser247Pro)

dbSNP: rs63750948
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075833 SCV000106847 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000629770 SCV000750726 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-07-12 criteria provided, single submitter clinical testing 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 expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 90342). This missense change has been observed in individuals with Lynch syndrome (PMID: 12200596, 15849733, 16083711, 16216036, 22736432, 27435373, 30521064). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 247 of the MLH1 protein (p.Ser247Pro). Experimental studies have shown that this missense change affects MLH1 function (PMID: 16083711, 17594722). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV001183309 SCV001349014 pathogenic Hereditary cancer-predisposing syndrome 2020-08-31 criteria provided, single submitter clinical testing This missense variant replaces serine with proline at codon 247 in the MutS interacting domain of the MLH1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ‚â•0.7, PMID: 27666373). Functional studies have shown that this variant decreased protein expression, localization and impaired mismatch repair activity (PMID: 16083711, 21120944, 22736432). This variant has been reported in multiple individuals affected with colorectal cancer and Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC) (PMID: 12200596, 15849733, 16083711, 16216036, 18383312, 21404117, 22736432, 27435373, 31118792). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics RCV001183309 SCV002671209 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-16 criteria provided, single submitter clinical testing The p.S247P variant (also known as c.739T>C), located in coding exon 9 of the MLH1 gene, results from a T to C substitution at nucleotide position 739. The serine at codon 247 is replaced by proline, an amino acid with similar properties. This alteration has been reported in multiple individuals whose colorectal tumors demonstrate high microsatellite instability and loss of MLH1 expression on immunohistochemistry in Lynch syndrome/HNPCC families meeting Amsterdam criteria (Ward R et al. J. Cancer Res. Clin. Oncol. 2002 Aug;128:403-11; Mangold E et al. J. Pathol. 2005 Dec;207:385-95; Hardt K et al. Fam. Cancer. 2011 Jun;10:273-84). Functional assays demonstrated reduced MMR activity and expression for p.S247P compared to wild-type MLH1 (Raevaara TE et al. Gastroenterology. 2005 Aug;129:537-49). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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