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

dbSNP: rs63750948

Total submissions: 4

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629770	SCV000750726	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-05-20	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 12200596, 15849733, 16083711, 16216036, 22736432, 27435373, 30521064; Invitae). Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. ClinVar contains an entry for this variant (Variation ID: 90342). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt MLH1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 16083711, 17594722). For these reasons, this variant has been classified as 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.