3-37017551-T-G

Variant names:

• chr3-37017551-T-G
• rs1553646683
• NM_000249.4:c.836T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PP3_Moderate BP6

The NM_000249.4(MLH1):​c.836T>G​(p.Val279Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V279L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.70
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 35 uncertain in NM_000249.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• BP6: Variant 3-37017551-T-G is Benign according to our data. Variant chr3-37017551-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446501.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000249.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	NM_000249.4	MANE Select	c.836T>G	p.Val279Gly	missense	Exon 10 of 19	NP_000240.1
	MLH1	NM_001354628.2		c.836T>G	p.Val279Gly	missense	Exon 10 of 18	NP_001341557.1
	MLH1	NM_001354629.2		c.737T>G	p.Val246Gly	missense	Exon 9 of 18	NP_001341558.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.836T>G	p.Val279Gly	missense	Exon 10 of 19	ENSP00000231790.3
	MLH1	ENST00000456676.7	TSL:1	c.836T>G	p.Val279Gly	missense	Exon 10 of 17	ENSP00000416687.3
	MLH1	ENST00000413740.2	TSL:1	c.836T>G	p.Val279Gly	missense	Exon 10 of 15	ENSP00000416476.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome Uncertain:1 Benign:1

Mar 28, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The MLH1 variant designated as NM_000249.3:c.836T>G (p.Val279Gly is classified as likely benign. The probability for this variant being pathogenic was 0.08% based on a PolyPhen-2 score of 0.99 and MAPP of 2.32 (Thompson et al. 2013, PMID: 22949379), so a pretest probability of 10% for Bayesian analysis was used for analysis. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of pathogenicity of 0.1608 to 1 (Thompson et al. 2003, PMID:12900794), providing additional evidence against pathogenicity. Additionally, this variant is a missense variant in a gene where truncating variants are pathogenic. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives a 2% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MLH1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

May 31, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Aug 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 279 of the MLH1 protein (p.Val279Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma or prostate cancer (PMID: 30374176, 32923906). ClinVar contains an entry for this variant (Variation ID: 446501). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. Studies have shown that this missense change results in skipping of exon 10 and/or exons 10-11, and produces a non-functional protein and/or introduces a premature termination codon (Invitae). 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.

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V279G variant (also known as c.836T>G), located in coding exon 10 of the MLH1 gene, results from a T to G substitution at nucleotide position 836. The valine at codon 279 is replaced by glycine, an amino acid with dissimilar properties. This alteration was identified in an individual diagnosed with melanoma at age 61 who also had a family history of breast cancer (Tsai GJ et al. Genet Med, 2019 06;21:1435-1442). This variant was also identified in 1/317 men in a metastatic prostate cancer cohort undergoing hereditary cancer genetic testing (Boyle JL et al. JCO Precis Oncol, 2020 Mar;4:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.84	L
PhyloP100		7.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.80		Loss of stability (P = 0.0185)
MVP		0.96
MPC		0.45
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.77
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1553646683; hg19: chr3-37059042;