chr3-37048578-T-G

Position:

• chr3-37048578-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000249.4(MLH1):​c.1958T>G​(p.Leu653Arg) 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 Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L653L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.70

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]

MLH1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 3-37048578-T-G is Pathogenic according to our data. Variant chr3-37048578-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 89957.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37048578-T-G is described in Lovd as [Likely_pathogenic]. Variant chr3-37048578-T-G is described in Lovd as [Pathogenic]. Variant chr3-37048578-T-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1958T>G	p.Leu653Arg	missense_variant	17/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1958T>G	p.Leu653Arg	missense_variant	17/19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 24, 2023

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 17510385, 23403630]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Lynch syndrome 1 Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 13, 2018

Variant reclassification due to new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probability > 0.95 (0.990) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 09, 2019

This sequence change replaces leucine with arginine at codon 653 of the MLH1 protein (p.Leu653Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. Based on a multifactorial likelihood algorithm using genetic, clinical, in silico and functional data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect MLH1 protein function (PMID: 17510385, 21952876, 17210669, 23403630). This variant has been observed in individuals with clinical features of Lynch syndrome in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89957). This variant is not present in population databases (ExAC no frequency). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2023

The p.L653R variant (also known as c.1958T>G), located in coding exon 17 of the MLH1 gene, results from a T to G substitution at nucleotide position 1958. The leucine at codon 653 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in individuals suspected of having HNPCC/Lynch syndrome and in individuals whose Lynch-associated tumors either displayed high microsatellite instability (MSI-H) or loss of MLH1 on immunohistochemistry (Earle JS et al. J Mol Diagn, 2010 Jul;12:433-40; Fan Y et al. Biochem. Genet., 2012 Feb;50:84-93; Stojcev Z et al. Acta Biochim. Pol., 2013 Jun;60:195-8; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Ambry internal data). In studies performed in yeast, this alteration displayed no dominant mutator phenotype and the yeast equivalent allele, p.L666R, was shown to have a higher mutator rate compared to wild type (Takahashi M et al. Cancer Res., 2007 May;67:4595-604; Wanat JJ et al. Hum. Mol. Genet., 2007 Feb;16:445-52). This alteration also demonstrated deficient mismatch repair activity in two different in vitro complementation assays and protein expression as well as interactions with PMS2 were shown to be reduced (Takahashi M et al. Cancer Res., 2007 May;67:4595-604; Fan Y et al. Biochem. Genet., 2012 Feb;50:84-93; Hinrichsen I et al. Clin. Cancer Res., 2013 May;19:2432-41). In another study, this alteration was analyzed in a mini gene assay using three different cell lines and no aberrant splicing was seen (Lastella P et al. BMC Genomics, 2006 Sep;7:243). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;.;.;.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;.;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.99
MVP		0.98
MPC		0.48
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.97

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: rs63751202; hg19: chr3-37090069;