NM_000249.4:c.1521G>C

Variant names:

• chr3-37028895-G-C
• rs863224633
• NM_000249.4:c.1521G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000249.4(MLH1):​c.1521G>C​(p.Leu507Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.76

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1521G>C	p.Leu507Phe	missense_variant	Exon 13 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1521G>C	p.Leu507Phe	missense_variant	Exon 13 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251414 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1

Nov 15, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Nov 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 507 of the MLH1 protein (p.Leu507Phe). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with colorectal polyps and colon cancer (PMID: 25477341). ClinVar contains an entry for this variant (Variation ID: 216330). 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 with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 25477341). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 25477341). 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	Benign	0.17
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;.;.;T;D
Eigen	Benign	0.10
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D;.;.;.;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0060	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.043	D;D;D;D;D;D;D;T
Polyphen		0.63	P;.;.;.;.;.;.;.
Vest4		0.54
MutPred		0.37		Loss of helix (P = 0.0017);.;.;.;.;.;.;.;
MVP		0.93
MPC		0.28
ClinPred		0.77	D
GERP RS		3.0
Varity_R		0.39
gMVP		0.26

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: rs863224633; hg19: chr3-37070386;