3-36993602-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000249.4(MLH1):c.55A>T(p.Ile19Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I19L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 8.85

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
Lynch syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
Lynch syndrome 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 59 uncertain in NM_000249.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 3-36993602-A-T is Pathogenic according to our data. Variant chr3-36993602-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 90274.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.55A>T	p.Ile19Phe	missense_variant	Exon 1 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.55A>T	p.Ile19Phe	missense_variant	Exon 1 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Carcinoma of colon

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The p.Ile19Phe variant has been previously identified in 3 of 102 probands with colorectal or endometrial cancer (Kurzawski 2002, Andrew 2002, Perera 2010). In one study, this variant was demonstrated to segregate with colon cancer in two individuals, increasing the likelihood this variant is pathogenic (Andrew 2002). In addition, this variant was previously identified in 1 family from our laboratory with a striking history of Lynch syndrome related tumors, three affected individuals with the variant, and in 5 other affected individuals who were not tested for the variant (but at least two are obligate carriers). MSI-H tumor was demonstrated in several of these individuals but MLH1 was shown to be intact by IHC. A second family was also identified by our laboratory and this variant was shown to segregate with disease in 2 affected individuals and the tumours analyzed were demonstrated to be MSI high. In addition, the p.Ile19 residue is conserved across mammals and lower species and in-silico data (AlignGVGD, SIFT) suggest this alteration may impact the protein. However, this information is not predictive enough to determine pathogenicity. This variant is listed in dbSNP (ID#: rs63750648) as coming from a "Clinical Source" with no frequency information and is not informative for assessing its frequency in the population. In summary, based on the above evidence this variant meets our laboratory's criteria to be classified as pathogenic. -

Hereditary nonpolyposis colon cancer

Pathogenic:1

May 12, 2025

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MLH1 c.55A>T (p.Ile19Phe) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.55A>T has been observed in multiple individuals affected with clinical features of Lynch Syndrome (e.g. Kurzawski_2002, Espenschied_2017, Andrew_2002, Yurgelun_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significantly impaired mismatch repair function (Ellison_2004). The following publications have been ascertained in the context of this evaluation (PMID: 12537657, 15475387, 28514183, 12362047, 28135145). ClinVar contains an entry for this variant (Variation ID: 90274). Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome 1

Pathogenic:1

Jun 13, 2018

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

Multifactorial likelihood analysis posterior probability > 0.95 (0.997) -

not provided

Pathogenic:1

Sep 01, 2020

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with colorectal or other Lynch-associated cancers meeting revised Bethesda or Amsterdam II criteria (Andrew 2002, Kurzawski 2002, Perera 2010, Yurgleun 2017); Not observed in large population cohorts (Lek 2016); Published functional studies demonstrate partial loss of mismatch repair function (Ellison 2004); 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, 30212499, 15475387, 29478780, 20864636, 12362047, 12537657, 28135145, 26333163, 26248088, 31857677, 31391288) -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 19 of the MLH1 protein (p.Ile19Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome and/or colorectal cancer (PMID: 12362047, 12537657, 20864636, 28135145, 28514183, 31857677). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. ClinVar contains an entry for this variant (Variation ID: 90274). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MLH1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 15475387). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Mar 28, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.I19F variant (also known as c.55A>T), located in coding exon 1 of the MLH1 gene, results from an A to T substitution at nucleotide position 55. The isoleucine at codon 19 is replaced by phenylalanine, an amino acid with similar properties. This alteration has been identified in multiple individuals with Lynch syndrome-related cancers whose families were either suspicious for Lynch syndrome or met Amsterdam criteria (Andrew SE et al. Genet.Test. 2002;6(4):319-22; Kurzawski G et al. J. Med. Genet. 2002 Oct;39:e65; Perera S et al. J. Molec. Diagnost. 2010 Nov;12(6):757-764; Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35(10):1086-1095; Ambry internal data). This variant has been identified in a proband who met Amsterdam I criteria for Lynch syndrome and tumor demonstrated high microsatellite instability (Ambry internal data). In addition, a segregation study conducted in our laboratory for this family demonstrated segregation with disease for four affected individuals across two generations. Protein functional analysis using a yeast-human hybrid assay demonstrated reduced mismatch repair function for this variant (Ellison AR et al. Nucleic Acids Res. 2004 Oct;32(18):5321-38). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.9

PhyloP100

8.8

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.95

MVP

0.98

MPC

0.50

ClinPred

1.0

GERP RS

6.0

PromoterAI

-0.097

Neutral

(source)

Varity_R

0.98

gMVP

0.94

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over