3-37040199-G-T

Variant names:

• chr3-37040199-G-T
• rs587779953
• NM_000249.4:c.1572G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BP6

The NM_000249.4(MLH1):​c.1572G>T​(p.Met524Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 9.74

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30633783).
• BP6: Variant 3-37040199-G-T is Benign according to our data. Variant chr3-37040199-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187310.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1572G>T	p.Met524Ile	missense_variant	Exon 14 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1572G>T	p.Met524Ile	missense_variant	Exon 14 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251158 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135732

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

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: 0.00000274 AC: 4 AN: 1461616 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1 Benign:1

Mar 12, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Mar 01, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Apr 10, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with isoleucine at codon 524 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549) and an individual affected with melanoma, prostate cancer, and basal cell carcinoma (PMID: 35932099). In a pancreatic case-control study, the variant was reported in 1/1005 pancreatic cancer cases and 67/23705 controls (PMID: 32980694). This variant has been identified in 1/251158 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. -

not specified Uncertain:1

Jan 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MLH1 c.1572G>T (p.Met524Ile) results in a conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251158 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1572G>T has been reported in the literature in an individual affected with Ovarian Cancer without strong evidence of causality (Pal_2012). This report does not provide unequivocal conclusions about association of the variant with Prostate Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 23047549). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Uncertain:1

Jun 17, 2024

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 methionine with isoleucine at codon 524 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549) and an individual affected with melanoma, prostate cancer, and basal cell carcinoma (PMID: 35932099). In a pancreatic case-control study, the variant was reported in 1/1005 pancreatic cancer cases and 67/23705 controls (PMID: 32980694). This variant has been identified in 1/251158 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. -

not provided Uncertain:1

Dec 18, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted MLH1 c.1572G>T at the cDNA level, p.Met524Ile (M524I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATT). This germline variant was observed once in a series of 1893 epithelial ovarian cancer cases (Pal 2012). MLH1 Met524Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MLH1 Met524Ile is located in the region of interaction with EXO1 and PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2010, Andersen 2012). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MLH1 Met524Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Benign	0.84
DEOGEN2	Uncertain	0.55	D;.;.;.;.;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.013
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;T;.;.;.;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.3	L;.;.;.;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.86	N;N;N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.88	T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;D
Polyphen		0.0030	B;.;.;.;.;.;.
Vest4		0.66
MutPred		0.38		Loss of catalytic residue at V520 (P = 0.0492);.;.;.;.;.;.;
MVP		0.84
MPC		0.073
ClinPred		0.38	T
GERP RS		5.7
Varity_R		0.21
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs587779953; hg19: chr3-37081690;