3-37017590-T-C

Position:

• chr3-37017590-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The ENST00000231790.8(MLH1):​c.875T>C​(p.Leu292Pro) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L292M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 ENST00000231790.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in ENST00000231790.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.875T>C	p.Leu292Pro	missense_variant	10/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.875T>C	p.Leu292Pro	missense_variant	10/19	1	NM_000249.4	ENSP00000231790	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing;curation

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Sep 10, 2021

Data included in classification: Revel score 0.959. (PP3_sup) Not observed in gnomAD v2.1. (PM2_sup) UK Family #1: Proband colorectal cancer at ~28 years – MLH1/PMS2 loss on IHC, MLH promoter methylation normal. Somatic mismatch repair panel: MLH1 LOH detected, MLH1 c.875T>C p.(Leu292Pro) 79% VAF (NCC: 30-50%); Literature Family #1: Pagenstecher et al 2006 (PMID: 16341550). Proband colorectal cancer at 34 years, father colorectal cancer at 75 years, grandfather colorectal cancer at 39 years. Proband’s tumour MSI high, MLH1 IHC loss (PMS2 IHC not examined, no MLH1 methylation results); Literature Family #2: Muller et al 2004 (PMID: 15507669). Proband colorectal cancer at 46. Proband’s tumour MSI high, MLH1 IHC loss (PMS2 IHC result not stated, no MLH1 methylation results). (PP4_str). Additional information (not included in classification): Literature Families #3-5: Kurzawski et al 2006 (PMID: 16451135) 3 observations in Polish families with a clinical diagnosis of HNPCC. InSiGHT classification class 3 – uncertain due to insufficient evidence 05/09/2013 Invitae class 3 uncertain significance (2018) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 292 of the MLH1 protein (p.Leu292Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 16341550; Invitae). ClinVar contains an entry for this variant (Variation ID: 90404). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 18383312). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The p.L292P variant (also known as c.875T>C), located in coding exon 10 of the MLH1 gene, results from a T to C substitution at nucleotide position 875. The leucine at codon 292 is replaced by proline, an amino acid with similar properties. This alteration has been identified in multiple individuals that met clinical criteria for Lynch syndrome (Kurzawski G et al. J. Med. Genet., 2002 Oct;39:E65; Pagenstecher C et al. Hum. Genet., 2006 Mar;119:9-22; Hardt K et al. Fam. Cancer, 2011 Jun;10:273-84; Ambry internal data). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;.;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.016	D;D;D;D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D;D;T;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.97
MutPred		0.72		Loss of stability (P = 0.0081);.;.;.;.;.;.;
MVP		0.97
MPC		0.50
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs63750517; hg19: chr3-37059081;