3-36996633-C-A

Position:

• chr3-36996633-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000231790.8(MLH1):​c.131C>A​(p.Ser44Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S44F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 ENST00000231790.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.74

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in ENST00000231790.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-36996633-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17079.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 3-36996633-C-A is Pathogenic according to our data. Variant chr3-36996633-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 619504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996633-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.131C>A	p.Ser44Tyr	missense_variant	2/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.131C>A	p.Ser44Tyr	missense_variant	2/19	1	NM_000249.4	ENSP00000231790	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Palindrome, Gene Kavoshgaran Aria

Sep 16, 2024

- -

Lynch syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

May 01, 2018

MLH1 NM_000249.3:c.131C>A has a 99.6% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2019

The p.S44Y variant (also known as c.131C>A), located in coding exon 2 of the MLH1 gene, results from a C to A substitution at nucleotide position 131. The serine at codon 44 is replaced by tyrosine, an amino acid with dissimilar properties. In one study, protein functional analysis was performed in assays using a hybrid human-yeast MLH1 gene and p.S44Y demonstrated significantly reduced mismatch repair activity (Ellison AR et al. Nucleic Acids Res., 2004 Oct;32:5321-38). Another alteration at the same codon, p.S44F, has been reported as pathogenic based on identification in individuals meeting clinical criteria for HNPCC/Lynch syndrome, segregation with disease, and deficient mismatch repair activity in functional studies (Bronner CE, Nature 1994 Mar; 368(6468):258-61; Tannergård P, Cancer Res. 1995 Dec; 55(24):6092-6; Salahshor S et al. Lab. Invest., 2001 Apr;81:535-41; de Jong AE et al. Clin. Cancer Res., 2004 Feb;10:972-80; Lagerstedt Robinson K et al. J. Natl. Cancer Inst., 2007 Feb;99:291-9; Takahashi M, Cancer Res. 2007 May; 67(10):4595-604; Drost M et al. Hum. Mutat., 2010 Mar;31:247-53). Based on an internal structural assessment, p.S44Y leads to general local structural disruption of a structurally sensitive region (Guarné A et al. EMBO J., 2001 Oct;20:5521-31). This variant was identified as somatic in conjunction with loss of heterozygosity of MLH1 in Lynch syndrome-related tumors demonstrating MMR deficiency by IHC (Shirts BH et al. Am. J. Hum. Genet. 2018 07;103:19-29; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved through mammals, but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.90		Loss of ubiquitination at K43 (P = 0.1287);
MVP		0.92
MPC		0.43
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.91

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: rs63751109; hg19: chr3-37038124;