rs121912957

Variant names:

• chr3-36996633-C-A
• rs63751109
• NM_000249.4:c.131C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-36996633-C-A
• chr3-36996633-C-G
• chr3-36996633-C-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000249.4(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 NM_000249.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.74
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Lynch syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 36 uncertain in NM_000249.4
• 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 VariationId 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 619504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.131C>A	p.Ser44Tyr	missense_variant	Exon 2 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.131C>A	p.Ser44Tyr	missense_variant	Exon 2 of 19	1	NM_000249.4	ENSP00000231790.3

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

Sep 16, 2024

Palindrome, Gene Kavoshgaran Aria

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Pathogenic:1

May 01, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 27, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		4.7
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
Mutation Taster		=26/74	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63751109; hg19: chr3-37038124;