rs63751703

Positions:

• chr3-37040191-C-G
• chr3-37040191-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000249.4(MLH1):​c.1564C>G​(p.Arg522Gly) variant causes a missense change involving the alteration of a 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. R522Q) has been classified as Likely benign.

• 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: 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1564C>G	p.Arg522Gly	missense_variant	14/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1564C>G	p.Arg522Gly	missense_variant	14/19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Labcorp Genetics (formerly Invitae), Labcorp

May 20, 2023

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 522 of the MLH1 protein (p.Arg522Gly). 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. 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. ClinVar contains an entry for this variant (Variation ID: 483549). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2024

The p.R522G variant (also known as c.1564C>G), located in coding exon 14 of the MLH1 gene, results from a C to G substitution at nucleotide position 1564. The arginine at codon 522 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not 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	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.81	D;.;.;.;.;.;D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;.;.;.;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.013	D;D;D;D;D;D;D
Sift4G	Uncertain	0.036	D;T;T;T;T;D;D
Polyphen		0.16	B;.;.;.;.;.;.
Vest4		0.58
MutPred		0.44		Gain of sheet (P = 0.0344);.;.;.;.;.;.;
MVP		0.92
MPC		0.091
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs63751703; hg19: chr3-37081682;