rs41295284

chr3-37047607-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1 PP3_Moderate BP6_Very_Strong

The NM_000249.4(MLH1):c.1820T>A(p.Leu607His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L607I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:15
• Conservation: PhyloP100: 7.81

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 -4 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, 16 uncertain in NM_000249.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• BP6: Variant 3-37047607-T-A is Benign according to our data. Variant chr3-37047607-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 89895.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37047607-T-A is described in Lovd as [Likely_benign]. Variant chr3-37047607-T-A is described in Lovd as [Benign]. Variant chr3-37047607-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.1820T>A	p.Leu607His	missense_variant	16/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.1820T>A	p.Leu607His	missense_variant	16/19	1	NM_000249.4	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152188 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000187 AC: 47 AN: 251378 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000194 AC: 284 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.000205 AC XY: 149 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000230

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152306 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74474

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:15

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 13, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant reported in 10 papers with functional data supporting non-pathogenic. Max MAF in ExAC is 0.04%. Classified by InSiGHT as Likely Benign (3 stars in ClinVar). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 27, 2021	Variant summary: MLH1 c.1820T>A (p.Leu607His) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 254496 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.00018 vs 0.00071), allowing no conclusion about variant significance. c.1820T>A has been reported in the literature in individuals affected with microsatellite stable (MSS) colorectal cancer, Lynch Syndrome or Lynch-syndrome associated cancers (e.g. Fidalgo_2000, Cravo_2002, Barnetson_2008, Valentin_2011, Castillejo_2014 ), including a family showing lack of co-segregation (Perez-Cabornero 2013). A recent study reporting tumour characteristic likelihood ratio (TCLR) for this variant, classified it as likely benign (Li_2020). The variant has been functionally characterized and shown to have no effect on splicing (Tournier 2008, Borras 2012) and MMR activity (Takahashi 2007, Houlleberghs_2020). One study (Xie 2010) indicated that the variant affects FANCJ binding which could play a role in cancer and/or chemoresistance due to a delay in MMR signaling. However, the conclusions drawn from this study remain speculative and do not allow an estimation of the risk associated with this variant. Therefore, the clinical and functional data do not allow any conclusion about variant significance. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.4137_4141delGATTA, p.Ile1380Argfs*21), providing supporting evidence for a benign role. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments and a majority consensus towards a likely benign outcome. Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	Dec 18, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 09, 2020	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 07, 2018	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 26, 2020	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 26, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2020	This variant is associated with the following publications: (PMID: 19389263, 17510385, 18561205, 20978114, 10713887, 11839723, 21681552, 23523604, 22949387, 18566915, 23588873, 22736432, 21056691, 18033691, 15365995, 11369138, 25871441, 20978117, 26637282, 23741719, 17192056, 24933000, 15222003, 26926912, 31784484) -

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 05, 2023

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 15, 2022

- -

Lynch syndrome Benign:1

Likely benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability 0.001-0.049 -

MLH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;.;.;.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.1	D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.83
MVP		0.96
MPC		0.45
ClinPred		0.56	D
GERP RS		5.3
Varity_R		0.92
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs41295284; hg19: chr3-37089098; COSMIC: COSV105856838;