Submissions for variant NM_000249.4(MLH1):c.1309C>G (p.Pro437Ala)

dbSNP: rs587782273

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131128	SCV000186060	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	The p.P437A variant (also known as c.1309C>G), located in coding exon 12 of the MLH1 gene, results from a C to G substitution at nucleotide position 1309. The proline at codon 437 is replaced by alanine, an amino acid with highly similar properties. This alteration was seen in 0/732 breast cancer patients, 0/189 colorectal cancer patients and 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000588028	SCV000211103	uncertain significance	not provided	2019-12-03	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 27150160)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556437	SCV000625056	benign	Hereditary nonpolyposis colorectal neoplasms	2024-11-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131128	SCV000689802	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 437 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals affected with ovarian, fallopian tube, or peritoneal carcinomas (PMID: 27150160). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588028	SCV000696105	uncertain significance	not provided	2017-02-13	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.1309C>G (p.Pro437Ala) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant is absent in 121382 control chromosomes. It has been reported in one extrauterine Mllerian carcinoma sample without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, because of lack of clinical and functional data, this variant is classified as VUS.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588028	SCV000885701	uncertain significance	not provided	2017-06-16	criteria provided, single submitter	clinical testing