3-37047639-AA-GC

Variant names:

• chr3-37047639-AA-GC
• rs35502531
• NM_000249.4:c.1852_1853delAAinsGC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM2 PM5 BP6_Very_Strong

The NM_000249.4(MLH1):​c.1852_1853delAAinsGC​(p.Lys618Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K618E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:24 O:1
• Conservation: PhyloP100: 7.33

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-37047639-AA-ATTCTT is described in Lovd as [Pathogenic].
• BP6: Variant 3-37047639-AA-GC is Benign according to our data. Variant chr3-37047639-AA-GC is described in ClinVar as [Benign]. Clinvar id is 17089.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1852_1853delAAinsGC	p.Lys618Ala	missense_variant		ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1852_1853delAAinsGC	p.Lys618Ala	missense_variant		1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:24 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:7 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 31, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -
Uncertain significance, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 29, 2021	- -

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Aug 01, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 06, 2024	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Vantari Genetics	Jan 25, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 03, 2018	- -

not provided Benign:4

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MLH1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Lynch syndrome Benign:2

Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Multifactorial likelihood analysis posterior probability <0.001 -
Benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 23, 2020	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 22, 2023

- -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Lys618Ala variant has been previously reported in the literature. It has been identified in 48/8212 (Freq: 0.006) proband chromosomes from families with colorectal cancer and or other cancer types and in 29/6204 (Freq: 0.005) control chromosomes, increasing the likelihood that this is a polymorphism (Auclair_2006_16395668; Barnetson_2008_18033691; Belvederesi_2006_16724012; Bianchi_2007_17250665; Fearnhead_2004_15520370; Fidalgo_2000_10713887; Gille_2002_12373605; Hampel_2006_16885385; Hedge_2005_16237223; Hudler_2004_15099349; Papp_2007_17569143; Perera_2007_18205192; Pinol_2005_15855432; Rubio-Del-Campo_2007_18325052; Scott_2001_11112663; Steinke_2008_18301448; Syngal_1999_10422993; Ward_2002_12200596; Weber_1997_9288790; Wolf_200515926618; Wijnen_1997_9311737; Tannergard_1995_8521398). Contradictory evidence exists regarding the functional significance of this variant. In vitro studies have demonstrated that the p.Lys618Ala substitution results in an 85% reduction in efficiency of binding to PMS2 and that it was unable to reverse the mutator phenotype in an MLH1 deficient ovarian cancer cell line (Blasi_2006_16982745; Guerrette_1999_10037723). However, Perera et al (2007) demonstrated that the p.Lys618Ala variant did not appear to perturb the ability of MLH1 to heterodimerize with the PMS2 protein. Although, they also showed that the variant protein had a half-life that was significantly decreased compared to the wild-type protein (Perera_2007_18205192), suggesting that this variant may have some functional consequence. There is a significant evidence against the pathogenicity of this variant. Previous studies have identified p.Lys618Ala variant in patients with Microsatelite Stable colorectal carcinomas that expressed MLH1 (Farrington et al., 1998; Liu_1999_10598809; Mauillon et al., 1996; Muller-Koch_2001_11726306; Samowitz et al., 2001; Wolf_2005_15926618). Several studies report this variant in the presence of a second variant which was in some cases pathogenic. For example an out-of-frame splice mutation (a A>G at position –2 in intron 6 of the hMLH1-gene). The splice mutation caused skipping of exon 7 and was shared with a younger sibling who had three consecutive CRCs and gastric cancer, all associated with MSI (Liu_1999_10598809). In this case, the p.Lys618Ala variant did not co-segregate with disease (Tannergard_1995_8521398). Still in another study, the MSH2 protein product was demonstrated to be absent and the MLH1 protein product was present in one affected individual with this variant, increasing the likelihood that the p.Lys618Ala variant is not pathogenic (Pinol_2005_15855432). Steinke et al (2008_18301448) also identified this variant in the presence of a second variant in two individuals, one was a pathogenic stop codon (Syngal_1999_10422993). In summary, based on the above information, this variant is predicted to be benign. Although it is predicted benign we cannot rule out that it may contribute to or modify the clinical features observed in this individual. -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 10, 2021

- -

Lynch syndrome 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Muir-Torré syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Feb 01, 2025

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2025

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35502531; hg19: chr3-37089130; COSMIC: COSV104573019;