Submissions for variant NM_000249.4(MLH1):c.554T>G (p.Val185Gly)

dbSNP: rs63750515

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075761	SCV000106769	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Abrogated function, 1 MSI-H tumour & 1 tumour with MLH1 immunoloss, co-segregation with disease & absent in 1000 genomes. Multifactorial likelihood analysis posterior probability >0.99.
GeneDx	RCV000218149	SCV000279073	pathogenic	not provided	2020-10-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced protein expression, deficient MMR activity, abnormal subcellular localization, and reduced interaction with protein partners (Trojan 2002, Kondo 2003, Raevaara 2005, Takahashi 2007, Bouvet 2019); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with personal and family history of MLH1-associated cancers including those with tumor studies consistent with pathogenic variants in this gene (Kohonen-Corish 1996, Scott 2001, Raevaara 2005, Chao 2008, Toon 2013, Chubb 2015); This variant is associated with the following publications: (PMID: 11112663, 30212499, 12810663, 17594722, 21120944, 22949387, 24362816, 9697702, 25525159, 16083711, 17510385, 11781295, 18383312, 25559809, 17192056, 30998989, 8808596, 23797718)
Invitae	RCV001385098	SCV001584840	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 185 of the MLH1 protein (p.Val185Gly). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 9697702, 11781295, 12810663, 16083711, 17510385, 17594722, 21120944). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). ClinVar contains an entry for this variant (Variation ID: 90272). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 8808596, 16083711). It has also been observed to segregate with disease in related individuals.
Ambry Genetics	RCV002345382	SCV002654031	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	The p.V185G variant (also known as c.554T>G), located in coding exon 7 of the MLH1 gene, results from a T to G substitution at nucleotide position 554. The valine at codon 185 is replaced by glycine, an amino acid with dissimilar properties. This alteration was identified in a proband with colorectal cancer diagnosed at age 43 whose family met Amsterdam I criteria; the colorectal tumor was MSI-H and had reduced MLH1 expression on IHC (Raevaara TE et al. Gastroenterology. 2005 Aug;129:537-49). This alteration also showed deficient mismatch repair activity in complementation assays (Trojan J et al. Gastroenterology. 2002 Jan;122:211-9; Kondo E et al. Cancer Res. 2003 Jun;63:3302-8; Takahashi M et al. Cancer Res. 2007 May;67:4595-604). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in 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.
Myriad Genetics, Inc.	RCV003452749	SCV004187224	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-17	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].