rs63751595

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_000249.4(MLH1):c.380G>A(p.Arg127Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 9.45

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a strand (size 9) in uniprot entity MLH1_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_000249.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-37004474-G-C is described in Lovd as [Likely_pathogenic].

PP5

Variant 3-37004474-G-A is Pathogenic according to our data. Variant chr3-37004474-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 90194.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37004474-G-A is described in Lovd as [Pathogenic]. Variant chr3-37004474-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.380G>A	p.Arg127Lys	missense_variant, splice_region_variant	4/19	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.380G>A	p.Arg127Lys	missense_variant, splice_region_variant	4/19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460908

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726884

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 13, 2023

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 31784484,]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16636019, 25559809, 31054147]. -

Lynch syndrome

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Oct 18, 2018

Last base of exon; Aberrant Splicing -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2021

This variant has been reported in several individuals and families affected with Lynch syndrome (PMID: 11112663, 16636019, 18625694, 25559809, 31054147, Invitae). ClinVar contains an entry for this variant (Variation ID: 90194). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with lysine at codon 127 of the MLH1 protein (p.Arg127Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2024

The c.380G>A pathogenic mutation (also known as p.R127K), located in coding exon 4 of the MLH1 gene, results from a G to A substitution at nucleotide position 380. The amino acid change results in arginine to lysine at codon 127, an amino acid with highly similar properties. This variant has been identified in a proband that met Amsterdam I/II criteria for Lynch syndrome and their tumor demonstrated high microsatellite instability (Chubb D et al. J Clin Oncol, 2015 Feb;33:426-32). This variant has been identified in probands who met Amsterdam I/II criteria for Lynch syndrome (Ambry internal data; Scott RJ et al. Am. J. Hum. Genet., 2001 Jan;68:118-127). This variant has also been identified in several probands whose Lynch syndrome-associated tumor demonstrated loss of MLH1/PMS2 expression by immunohistochemistry (Ambry internal data; Niessen RC et al. Gut, 2006 Dec;55:1781-8; Tian W et al. Int J Cancer, 2019 09;145:1290-1298; Li S et al. J. Med. Genet. 2020 Jan;57:62-69). This nucleotide position is highly conserved in available vertebrate species. This alteration occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Benign

0.93

DEOGEN2

Uncertain

0.45

T;.;T

Eigen

Benign

-0.14

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.40

T;T;T

MetaSVM

Uncertain

-0.081

MutationAssessor

Benign

-0.26

N;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.33

N;N;N

REVEL

Uncertain

0.55

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.069

B;.;.

Vest4

0.75

MutPred

0.51

Loss of methylation at R127 (P = 0.0254);.;.;

MVP

0.97

MPC

0.082

ClinPred

0.82

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.75

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.75

Position offset: 0

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