3-37017529-T-G

Position:

• chr3-37017529-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000249.4(MLH1):​c.814T>G​(p.Leu272Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L272F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0670

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_000249.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-37017530-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.814T>G	p.Leu272Val	missense_variant	10/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.814T>G	p.Leu272Val	missense_variant	10/19	1	NM_000249.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 12, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 272 of the MLH1 protein (p.Leu272Val). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 90385). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 17210669, 17510385, 31697235). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26761715). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The p.L272V variant (also known as c.814T>G), located in coding exon 10 of the MLH1 gene, results from a T to G substitution at nucleotide position 814. The leucine at codon 272 is replaced by valine, an amino acid with highly similar properties. In an in vitro complementation assay (human colon cancer cells), this alteration demonstrated a high (90.2%) level of normal MMR activity (Takahashi M et al. Cancer Res., 2007 May;67:4595-604). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.;.;.;.;.
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.40	N
LIST_S2	Pathogenic	0.98	D;D;.;.;.;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0050	D;D;D;D;D;T;D
Sift4G	Uncertain	0.010	D;D;D;D;D;T;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.78
MutPred		0.72		Gain of sheet (P = 0.0477);.;.;.;.;.;.;
MVP		0.95
MPC		0.36
ClinPred		0.81	D
GERP RS		1.7
Varity_R		0.37
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63751252; hg19: chr3-37059020;