3-36993656-G-C

Variant names:

• chr3-36993656-G-C
• rs63751012
• NM_000249.4:c.109G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000249.4(MLH1):​c.109G>C​(p.Glu37Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 9.49

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 13) in uniprot entity MLH1_HUMAN there are 19 pathogenic changes around while only 8 benign (70%) in NM_000249.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 3-36993656-G-C is Pathogenic according to our data. Variant chr3-36993656-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 231565.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.109G>C	p.Glu37Gln	missense_variant	Exon 1 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.109G>C	p.Glu37Gln	missense_variant	Exon 1 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome Pathogenic:1

Feb 07, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MLH1 p.E37K variant has been identified in an individual with a family history that meets current Amerstam criteria for Lynch syndrome. Testing performed on tumor tissue of a paitient with germline MLH1 p.E37K supports that this variant is likely pathogenic. Specifically, the germline MLH1 variant was detecting with loss of heterozygosity (LOH) of the second allele in the patient's tumor. Tumor screening showed the tissue was MSI-High with intact MLH1 protein expression by IHC. A different variant at the same codon of MLH1 (p.E37) has been observed as a double somatic mutation in a tumor tissue of a patient with endometrial adenocarcinoma that was microsatellite instability high, with intact MLH1 protein expression by IHC, and negative germline testing (UWMC internal data). This information suggests that mutations at codon 37 of the MLH1 protein may cause loss of protein function while leaving MLH1 protein staining intact on IHC. This variant has also been previously reported in a group of patients meeting Bethesda criteria, but occured in cis with a separate MLH1 frameshift mutation (PMID 25420488). This variant is not currently reported in population databases and occurs at a amino acid position that is conserved across species. -

Lung cancer Pathogenic:1

Jan 13, 2022

Molekularpathologisches Zentrum, Universitaetsklinikum Heidelberg

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 27, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E37Q variant (also known as c.109G>C), located in coding exon 1 of the MLH1 gene, results from a G to C substitution at nucleotide position 109. The glutamic acid at codon 37 is replaced by glutamine, an amino acid with highly similar properties. This variant was identified in an individual whose family history met Amsterdam criteria for Lynch syndrome and whose colon tumor displayed high microsatellite instability (MSI-H), but had normal MMR gene protein expression by immunohistochemistry (IHC) (Ambry internal data). This variant was also identified in the germline of an individual who had a family history of Lynch-associated cancers and a MSI-H endometrial tumor with MLH1 copy-neutral loss of heterozygosity (CN-LOH), but normal IHC (Ambry internal data). In a cohort of Indian patients with colorectal cancer meeting Bethesda criteria, this variant was reported in cis with an MLH1 frameshift mutation in an individual whose tumor demonstrated microsatellite instability and loss of MLH1 and PMS2 protein expression (Bashyam MD et al. Mol Carcinog. 2014 Nov 24). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly 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. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Jul 09, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with glutamine at codon 37 of the MLH1 protein (p.Glu37Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Lynch syndrome (PMID: 25420488). However, in that individual a truncating variant was also identified in cis in MLH1, and the impact of this c.109G>C variant is not known. ClinVar contains an entry for this variant (Variation ID: 231565). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	4.9	H
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.89		Loss of ubiquitination at K33 (P = 0.1113);
MVP		1.0
MPC		0.40
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs63751012; hg19: chr3-37035147; COSMIC: COSV51615011; COSMIC: COSV51615011;