rs748417604

Variant names:

• chr3-37008814-G-A
• rs748417604
• ENST00000458205.6:c.-270G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-37008814-G-A
• chr3-37008814-G-C
• chr3-37008814-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM5 PP3_Moderate

The NM_000249.4(MLH1):​c.454G>A​(p.Val152Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,459,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V152G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MLH1 NM_000249.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 8.85
• Publications: 10 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000249.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-37008815-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 579404.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.454G>A	p.Val152Met	missense_variant, splice_region_variant	Exon 6 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.454G>A	p.Val152Met	missense_variant, splice_region_variant	Exon 6 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251266 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1459994 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 726452

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1110364

Other (OTH) AF: 0.0000166 AC: 1 AN: 60326

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000549 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Oct 26, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted MLH1 c.454G>A at the cDNA level, p.Val152Met (V152M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has been observed in at least one individual with a personal and family history of colorectal cancer (Chubb 2015). MLH1 Val152Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Val152Met occurs at a position that is conserved across species and is located within the N-terminal ATPase domain (Anderson 2012). Protein based in silico analyses predict that this variant is probably damaging to protein structure and function while splicing based models predict this variant to either weaken or destroy the natural splice acceptor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether MLH1 Val152Met is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Jan 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MLH1 c.454G>A (p.Val152Met) variant has been reported in the published literature in individuals with colon cancer (PMID: 25559809 (2015)), esophageal cancer (PMID: 30833958 (2019)), and breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MLH1)). The frequency of this variant in the general population, 0.000008 (2/251266 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:2

Aug 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with methionine at codon 152 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809), esophageal squamous cell carcinoma (PMID: 30833958), or breast cancer (PMID 34359559). This variant has been identified in 2/251266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.455T>G (p.Val152Gly), is considered to be disease-causing (ClinVar variation ID: 579404), suggesting that this position may be important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mar 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V152M variant (also known as c.454G>A), located in coding exon 6 of the MLH1 gene, results from a G to A substitution at nucleotide position 454. The valine at codon 152 is replaced by methionine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 6. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC) (Ambry internal data). In one study, this variant was observed in 1/626 Northern European patients with colorectal cancer diagnosed before age 56, who had at least one first-degree relative with colorectal cancer (Chubb D et al. J. Clin. Oncol. 2015 Feb;33(5):426-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lynch syndrome Uncertain:1

Dec 01, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with methionine at codon 152 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809), esophageal squamous cell carcinoma (PMID: 30833958), or breast cancer (PMID 34359559). This variant has been identified in 2/251266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Muir-Torré syndrome Uncertain:1

Apr 13, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MLH1 c.454G>A variant is classified as VUS (PS4_Supporting, PM2, PP3) The MLH1 c.454G>A variant is located in a splice region. The MLH1 c.454G>A variant is a single nucleotide change in exon 6/19 of the MLH1 gene, which is predicted to change the amino acid valine at position 152 in the protein to methionine. The variant has been reported in a patient with esophageal cancer and another with colon cancer (PMID:25559809, PMID:30833958) (PS4_Supporting). This variant is absent from population databases (PM2). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs748417604) and in the HGMD database (CM1913018). It has been reported as Uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 184683). -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Sep 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.1	H;.;.
PhyloP100		8.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D;N;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.80
MVP		0.97
MPC		0.39
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.49
gMVP		0.86
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.14		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: rs748417604; hg19: chr3-37050305; COSMIC: COSV51624525; COSMIC: COSV51624525;