rs566928243

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5BP6

The NM_000249.4(MLH1):c.2174G>A(p.Arg725His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,614,154 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R725C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000098 ( 1 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:7

Conservation

PhyloP100: 9.76

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:

MLH1 (HGNC:):

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-37050555-C-T is described in Lovd as [Pathogenic].

BP6

Variant 3-37050556-G-A is Benign according to our data. Variant chr3-37050556-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90082.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=8, Benign=3}. Variant chr3-37050556-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.2174G>A	p.Arg725His	missense_variant	19/19	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.2174G>A	p.Arg725His	missense_variant	19/19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000187

AC:

AN:

251152

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00358

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000978

AC:

143

AN:

1461816

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00394

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000585

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 11, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 16, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 01, 2022	- -

not specified

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2024	Variant summary: MLH1 c.2174G>A (p.Arg725His) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) 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 0.00019 in 251152 control chromosomes. However, the frequency at which the variant is found in the Ashkenazi Jewish population is higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (0.0036 vs 0.00071), suggesting the variant may be a polymorphism found in that population. c.2174G>A has been reported in the literature in individuals affected with colorectal, breast, endometrial and pancreatic cancers, without strong evidence for pathogenicity (eg. Chao_2008, Kraus_2015, Lipkin_2004, Shirts_2016, Abe_2019, Ozdemir_2019, Sung_2017, Tsaousis_2019, Solmaz_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, showing reduced expression, but overall reported the variant to be moderately functional (Arora_2017). The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 22290698, 28494185, 18383312, 32061754, 25142776, 15184898, 25503501, 30238922, 26845104, 33980423, 28961279, 31159747). ClinVar contains an entry for this variant (Variation ID: 90082). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 18, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 31, 2020	DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.2174G>A, in exon 19 that results in an amino acid change, p.Arg725His. This sequence change has been described in the gnomAD database with a relatively high frequency of 0.35% in the Ashkenazi Jewish sub-population (dbSNP rs566928243). The p.Arg725His change has been described in an individual with breast cancer (PMID: 28961279), an individual with endometrial cancer (PMID: 30238922), and an individual meeting criteria for genetic testing, however specific phenotypic information was not provided (PMID: 31159747). Additionally, a different amino acid change at the same location (p.Arg725Cys) has been reported in association with non-polyposis colorectal cancer (PMID: 18383312). The p.Arg725His change affects a highly conserved amino acid residue located in a domain of the MLH1 protein that is not known to be functional. The p.Arg725His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg725His change remains unknown at this time. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2024	Observed in individuals with colorectal cancer or polyps, breast cancer, or endometrial cancer (PMID: 18383312, 26845104, 28961279, 30238922, 25142776); Published functional studies are inconclusive: reduced protein expression, but cellular viability and DNA damage response (DDR) signaling similar to wild type (PMID: 28494185); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18383312, 25503501, 28125075, 22290698, 25142776, 15184898, 26269718, 26845104, 28961279, 22585170, 31159747, 30238922, 33980423, 32095738, 30883245, 28494185, 12799449, 20533529, 22753075) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Colorectal cancer, hereditary nonpolyposis, type 2

Uncertain:1Benign: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. -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 16, 2023	This variant is considered 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]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Nov 20, 2015

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D;.;.;.;D

M_CAP

Pathogenic

0.50

MetaRNN

Uncertain

0.69

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

M;.;.;.;.;.

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-4.1

D;.;D;D;D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0030

D;.;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.77

MutPred

0.79

Loss of MoRF binding (P = 0.0239);.;.;.;.;.;

MVP

0.96

MPC

0.41

ClinPred

0.79

GERP RS

5.4

Varity_R

0.87

gMVP

0.73

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

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