rs63751270

chr3-37048524-A-Gchr3-37048524-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000249.4(MLH1):c.1904A>G(p.Asn635Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N635K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.91

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 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000249.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.1904A>G	p.Asn635Ser	missense_variant	17/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.1904A>G	p.Asn635Ser	missense_variant	17/19	1	NM_000249.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251352 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460872 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726844

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 01, 2022	The p.N635S variant (also known as c.1904A>G), located in coding exon 17 of the MLH1 gene, results from an A to G substitution at nucleotide position 1904. The asparagine at codon 635 is replaced by serine, an amino acid with highly similar properties. This alteration was detected in one hereditary colon cancer family and was absent in 220 healthy controls (Blasi MF, Cancer Res. 2006 Sep; 66(18):9036-44). This amino acid position is highly 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 05, 2019	- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 635 of the MLH1 protein (p.Asn635Ser). This variant is present in population databases (rs63751270, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 16982745). ClinVar contains an entry for this variant (Variation ID: 89937). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be tolerated (PMID: 22290698). Experimental studies have shown that this missense change affects MLH1 function (PMID: 16982745). 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	0.11
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D;.;.;.;.;.
Eigen	Benign	0.041
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;D;.;.;.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.33	T;T;T;T;T;T
Sift4G	Benign	0.46	T;T;T;T;T;T
Polyphen		0.16	B;.;.;.;.;.
Vest4		0.55
MutPred		0.46		Gain of glycosylation at N635 (P = 0.0209);.;.;.;.;.;
MVP		0.89
MPC		0.061
ClinPred		0.35	T
GERP RS		4.7
Varity_R		0.53
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs63751270; hg19: chr3-37090015;