chr3-37004469-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_000249.4(MLH1):c.375A>G(p.Ala125Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,613,700 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 Likely benign (★★★).

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

MLH1
NM_000249.4 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel B:20

Conservation

PhyloP100: -1.40

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 3-37004469-A-G is Benign according to our data. Variant chr3-37004469-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 90183.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37004469-A-G is described in Lovd as [Likely_benign]. Variant chr3-37004469-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.4 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00065 (99/152364) while in subpopulation AMR AF= 0.00301 (46/15304). AF 95% confidence interval is 0.00231. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.375A>G	p.Ala125Ala	synonymous_variant	Exon 4 of 19	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.375A>G	p.Ala125Ala	synonymous_variant	Exon 4 of 19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.000650

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

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:

0.000632

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000609

AC:

153

AN:

251398

Hom.:

AF XY:

0.000567

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000581

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000515

AC:

753

AN:

1461336

Hom.:

Cov.:

AF XY:

0.000502

AC XY:

365

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00230

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000556

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000650

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000336

Hom.:

Bravo

AF:

0.000846

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:20

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MLH1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 07, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 06, 2022	- -

Colorectal cancer, hereditary nonpolyposis, type 2

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Nov 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 17, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 15, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 08, 2021	DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.925C>T, in exon 10 that results in an amino acid change, p.Arg309Cys. This sequence change has been described in the gnomAD database with a frequency of 0.09% in the European population (dbSNP rs138089183). The p.Arg309Cys change affects a poorly conserved amino acid residue located in a domain of the MUTYH protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg309Cys substitution. The c.925C>T sequence change has been identified in individuals with colorectal polyps and/or colorectal cancer (PMIDs: 19732775; 19527492, 27829682). Out et al., 2012, identified the p.Arg309Cys change in individuals with a personal and/or family history of breast cancer and in controls, without a statistically significant difference in the rates of detection between the two populations (PMID: 22297469). In vitro analyses of the p.Arg309Cys change have shown contradictory results. Goto et al., 2010, demonstrated that the variant retains normal glycosylase activity in vitro (PMID: 20848659). However, Brinkmeyer et al., 2015, and Komine et al., 2015, performed in vitro assays that demonstrated significant decreases in enzyme activity, binding activity to damaged DNA, and defective base excision repair activity (PMIDs: 26377631, 25820570). Due to these contrasting evidences, the clinical significance of the p.Arg309Cys change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 05, 2014	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 01, 2015	- -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 12, 2023

- -

Lynch syndrome

Benign:1

Likely benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Synonymous substitution with no effect on splicing, tested with NMD inhibitor -

MLH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MLH1 p.Ala125= variant was identified in dbSNP (ID: rs1800144 as With Likely benign allele), ClinVar (likely benign as reviewed by expert panel; 8x as benign or likely benign), Cosmic (1x), UMD-LSDB (9x, classified as neutral, co-occurred with pathogenic variants in MLH1 or MSH2 3x), Insight Colon Cancer Gene Variant Database (6x, as likely not pathogenic), and Mismatch Repair Genes Variant Database. The variant was also identified in control databases in 150 of 277158 chromosomes at a frequency of 0.0005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was identified in the following populations: African in 4 of 24038 chromosomes (freq: 0.0002), Other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 77 of 34418 chromosomes (freq: 0.002237), European Non-Finnish in 65 of 126642 chromosomes (freq: 0.0005), and Ashkenazi Jewish in 1 of 10150 chromosomes (freq: 0.0001); it was not observed in the East Asian, Finnish, or South Asian populations. The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The p.Ala125= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, one study using RT-PCR from patient RNA followed by sequencing did not detect aberrant splicing (Auclair 2006). In summary, the clinical significance of this variant cannot be determined with certainty at this time although the available information is suggestive of a benign role. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.0

DANN

Benign

0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over