3-37014544-C-T

Position:

chr3-37014544-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP3_Strong

The ENST00000231790.8(MLH1):c.790C>T(p.His264Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000141 in 1,558,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H264D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MLH1
ENST00000231790.8 missense, splice_region

Scores

Splicing: ADA: 0.9880

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 5.77

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 Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in ENST00000231790.8

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-37017506-A-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.790C>T	p.His264Tyr	missense_variant, splice_region_variant	9/19	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.790C>T	p.His264Tyr	missense_variant, splice_region_variant	9/19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250062

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000984

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000135

AC:

AN:

1406002

Hom.:

Cov.:

AF XY:

0.0000228

AC XY:

AN XY:

702876

show subpopulations

Gnomad4 AFR exome

AF:

0.0000310

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000470

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000942

Gnomad4 OTH exome

AF:

0.0000511

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

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:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 19, 2023	The p.H264Y variant (also known as c.790C>T), located in coding exon 9 of the MLH1 gene, results from a C to T substitution at nucleotide position 790. The amino acid change results in histidine to tyrosine at codon 264, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). In one functional study, the p.H264Y variant demonstrated restored cytotoxicity to methylation damage in a human colorectal cancer cell line; however, the mean survival score was between those of known damaging and neutral alterations leading to the tentative classification of "potentially neutral" (Bouvet D et al. Gastroenterology. 2019 08;157(2):421-431). This alteration has been reported in a Chinese male diagnosed with a MSI-H colorectal cancer at age 30y which demonstrated absent MLH1 protein expression on IHC. However, authors note that this alteration was detected in conjunction with the MLH1 p.T117M mutation, presumably on the same chromosome (in cis) as this patient's affected mother was also found to carry both alterations (Chan TL et al. J. Natl. Cancer Inst., 1999 Jul;91:1221-6; Lucci-Cordisco E et al. Cancer Biomark, 2006;2:11-27; Yuen ST et al. Oncogene, 2002 Oct;21:7585-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 17, 2022	This missense variant replaces histidine with tyrosine at codon 264 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies report conflicting results for this variant. One study assaying DNA damage tolerance found this variant to be functional (PMID: 30998989), while another study assaying DNA repair activity in mouse cells reported this variant as pathogenic (PMID: 31784484). This variant has been reported in individuals affected with colorectal cancer (PMID: 10413423, 30998989). This variant has been identified in 5/281464 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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 23, 2019

Variant summary: MLH1 c.790C>T (p.His264Tyr) results in a conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Despite the variant being located at the last nucleotide position in exon 9, 5/5 computational tools predict no significant impact on normal splicing. Additionally, no truncated protein product was detected in a patient sample carrying the variant, supporting the lack of impact of this variant on splicing (Chan_1999). The variant allele was found at a frequency of 1.6e-05 in 250062 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.790C>T has been reported in the literature in a mother and son with colorectal cancer who also carried another pathogenic variant MLH1 c.350C>T (p.T117M), providing supporting evidence for a benign role (Chan_1999, Yuen_2002). One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Bouvet_2019). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Colorectal cancer, hereditary nonpolyposis, type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Jul 27, 2023

This MLH1 missense variant has been reported in a mother and son who were both affected with colorectal cancer, and both of them had a second MLH1 variant (c.350C>T; p.Thr117Met) that is known to be pathogenic. c.790C>T (rs63751597) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 5/281464 total alleles; 0.002%; no homozygotes). It has been reported in ClinVar (Variation ID 90367). Two bioinformatic tools queried predict that this substitution would be damaging, and the histidine residue at this position is evolutionarily conserved across most of the species assessed. However, assays studying the effect of this variant on protein function have been inconclusive, with one study suggesting the variant is neutral and another suggesting a pathogenic role. While this variant changes the last nucleotide of exon 9, it is not predicted to affect normal exon 9 splicing, and at least one experimental study supports the lack of an effect on splicing. We consider the clinical significance of c.790C>T in MLH1 to be uncertain at this time. -

Lynch syndrome 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Ding PR Lab, Sun Yat-sen University Cancer Center

- -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Mar 24, 2024

This missense variant replaces histidine with tyrosine at codon 264 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies report conflicting results for this variant. One study assaying DNA damage tolerance found this variant to be functional (PMID: 30998989), while another study assaying DNA repair activity in mouse cells reported this variant as pathogenic (PMID: 31784484). This variant has been reported in individuals affected colorectal cancer (PMID: 10413423, 30998989). This variant has been identified in 5/281464 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. -

MLH1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 23, 2024

The MLH1 c.790C>T variant is predicted to result in the amino acid substitution p.His264Tyr. This variant has been reported in cis with a pathogenic MLH1 variant in a child and their mother, both with colorectal cancer (Chan et al. 1999. PubMed ID: 10413423). In vitro functional studies demonstrate a minimal effect on mismatch repair activity; however the mean survival score was potentially neutral and methylation tolerance showed minimal or no evidence of pathogenicity (Bouvet et al. 2019. PubMed ID: 30998989; Houlleberghs et al. 2019. PubMed ID: 31784484). It is interpreted as uncertain in ClinVar with multiple submitters in agreement (https://www.ncbi.nlm.nih.gov/clinvar/variation/90367/). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual and parent both with colorectal cancer who both also carried a pathogenic MLH1 variant (Chan et al., 1999); This variant is associated with the following publications: (PMID: 27498913, 23760103, 17192056, 12386821, 18383312, 34426522, 22753075, 21153778, 35031544, 31784484, 23403630, 10956410, 10413423, 30998989) -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 10, 2022

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 264 of the MLH1 protein (p.His264Tyr). This variant is present in population databases (rs63751597, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 10413423, 30998989). ClinVar contains an entry for this variant (Variation ID: 90367). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 30998989, 31784484). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 10413423). 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 breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Jan 09, 2024

. According to the ACMG standard criteria we chose these criteria: PM2 (supporting pathogenic): popmax:AFR popmax AF:4.82905e-05 popmax AC:2, PP3 (supporting pathogenic): CADD:29.9 REVEL: 0.911 BayesDEL:0.409449 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;.;.;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;.;.;.;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.8

H;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.6

D;D;D;D;D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0040

D;D;D;D;D;D;D

Sift4G

Uncertain

0.018

D;D;D;D;D;T;D

Polyphen

1.0

D;.;.;.;.;.;.

Vest4

0.83

MutPred

0.92

Gain of catalytic residue at L259 (P = 0.0603);.;.;.;.;.;.;

MVP

0.95

MPC

0.42

ClinPred

0.90

GERP RS

5.4

Varity_R

0.90

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.81

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

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