Submissions for variant NM_000249.4(MLH1):c.62C>T (p.Ala21Val)

dbSNP: rs63750706

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075787	SCV000106797	pathogenic	Lynch syndrome 1	2015-11-24	reviewed by expert panel	research
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269890	SCV001450227	pathogenic	not provided	2017-05-11	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000075787	SCV001499795	pathogenic	Lynch syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001269890	SCV001822700	likely pathogenic	not provided	2021-04-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: defects in mismatch repair (Houllenberghs 2020); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Cederquist 2004, Lagerstedt-Robinson 2016, Alqahtani 2017, Staninova-Stojovska 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; This variant is associated with the following publications: (PMID: 22753075, 31784484, 31942411, 14961575, 28643016, 27601186, 24362816)
Ambry Genetics	RCV002362709	SCV002657222	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-07-14	criteria provided, single submitter	clinical testing	The p.A21V variant (also known as c.62C>T), located in coding exon 1 of the MLH1 gene, results from a C to T substitution at nucleotide position 62. The alanine at codon 21 is replaced by valine, an amino acid with similar properties. This variant has been reported in multiple Lynch syndrome/HNPCC families to date with microsatellite unstable (MSI-H) tumors and absent MLH1 and/or PMS2 on immunohistochemistry (Cederquist K et al. Int. J. Cancer, 2004 Apr;109:370-6; Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835; Alqahtani M et al. Fam. Cancer, 2018 Apr;17:197-203; Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16). In an in vitro complementation assay, this variant was determined to be functionally deficient (Drost M et al. Genet Med, 2019 07;21:1486-1496). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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.
Myriad Genetics, Inc.	RCV003452755	SCV004189262	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30504929]. This variant is expected to disrupt protein structure [Myriad internal data].
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001269890	SCV005199134	pathogenic	not provided	2023-04-25	criteria provided, single submitter	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162488	SCV002758040	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research