3-37040192-G-T

Variant names:

• chr3-37040192-G-T
• rs63751630
• NM_000249.4:c.1565G>T

Variant summary

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

The NM_000249.4(MLH1):​c.1565G>T​(p.Arg522Leu) variant causes a missense change. 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, single submitter U:1
• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1565G>T	p.Arg522Leu	missense_variant	Exon 14 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1565G>T	p.Arg522Leu	missense_variant	Exon 14 of 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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 14, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R522L variant (also known as c.1565G>T), located in coding exon 14 of the MLH1 gene, results from a G to T substitution at nucleotide position 1565. The arginine at codon 522 is replaced by leucine, an amino acid with dissimilar properties. This alteration, designated "codon 522, CGG to CTG, Arg to Leu" was identified in an MSI-L sporadic breast tumor demonstrating reduced expression of MLH1 protein by IHC (Murata H et al. Oncogene, 2002 Aug;21:5696-703). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). 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	0.18
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;.;.;.;.;D
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.043
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;D;.;.;.;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.018	D;D;D;D;D;D;D
Sift4G	Uncertain	0.045	D;T;T;T;T;D;D
Polyphen		0.016	B;.;.;.;.;.;.
Vest4		0.63
MutPred		0.47		Gain of sheet (P = 0.0344);.;.;.;.;.;.;
MVP		0.93
MPC		0.082
ClinPred		0.78	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.59

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: rs63751630; hg19: chr3-37081683;