NM_000249.4(MLH1):c.188A>T (p.Asp63Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 9, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001805680.6

Allele description [Variation Report for NM_000249.4(MLH1):c.188A>T (p.Asp63Val)]

NM_000249.4(MLH1):c.188A>T (p.Asp63Val)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.188A>T (p.Asp63Val)

HGVS:

NC_000003.12:g.36996690A>T
NG_007109.2:g.8341A>T
NG_008418.1:g.1615T>A
NM_000249.4:c.188A>TMANE SELECT
NM_001167617.3:c.-102A>T
NM_001167618.3:c.-536A>T
NM_001167619.3:c.-444A>T
NM_001258271.2:c.188A>T
NM_001258273.2:c.-517+3027A>T
NM_001258274.3:c.-681A>T
NM_001354615.2:c.-439A>T
NM_001354616.2:c.-444A>T
NM_001354617.2:c.-536A>T
NM_001354618.2:c.-536A>T
NM_001354619.2:c.-536A>T
NM_001354620.2:c.-102A>T
NM_001354621.2:c.-629A>T
NM_001354622.2:c.-742A>T
NM_001354623.2:c.-723+2800A>T
NM_001354624.2:c.-639A>T
NM_001354625.2:c.-542A>T
NM_001354626.2:c.-639A>T
NM_001354627.2:c.-639A>T
NM_001354628.2:c.188A>T
NM_001354629.2:c.188A>T
NM_001354630.2:c.188A>T
NP_000240.1:p.Asp63Val
NP_001245200.1:p.Asp63Val
NP_001341557.1:p.Asp63Val
NP_001341558.1:p.Asp63Val
NP_001341559.1:p.Asp63Val
LRG_216t1:c.188A>T
LRG_216:g.8341A>T
NC_000003.11:g.37038181A>T
NM_000249.3:c.188A>T

Protein change:

D63V

Links:

dbSNP: rs1064795693

NCBI 1000 Genomes Browser:

rs1064795693

Molecular consequence:

NM_001167617.3:c.-102A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-536A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-444A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-681A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-439A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-444A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-536A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-536A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-536A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-102A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-629A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-742A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-639A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-542A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-639A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-639A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3027A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2800A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.188A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.188A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.188A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.188A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.188A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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esv34033 (0)
GEO DataSets
Serratia sp. JG-4-2 16S ribosomal RNA gene, partial sequence
Serratia sp. JG-4-2 16S ribosomal RNA gene, partial sequence
gi|359744439|gb|JN381535.1|

Nucleotide
Homo sapiens thioredoxin domain containing 11, mRNA (cDNA clone IMAGE:3864677), ...
Homo sapiens thioredoxin domain containing 11, mRNA (cDNA clone IMAGE:3864677), complete cds
gi|15489247|gb|BC013727.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002053718	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 9, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 2722481, 23733757, 34172528, 25741868
SCV002722481	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 26, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17569143, 23733757 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002053718

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 9, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002722481

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jul 26, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Fatal knowledge? Prenatal diagnosis and sex selection.

Wertz DC, Fletcher JC.

Hastings Cent Rep. 1989 May-Jun;19(3):21-7.

PubMed [citation]

PMID:: 2722481

Prevalence and spectrum of DNA mismatch repair gene variation in the general Chinese population.

Zhang L, Qin Z, Huang T, Tam B, Ruan Y, Guo M, Wu X, Li J, Zhao B, Chian JS, Wang X, Wang L, Wang SM.

J Med Genet. 2022 Jul;59(7):652-661. doi: 10.1136/jmedgenet-2021-107886. Epub 2021 Jun 25.

PubMed [citation]

PMID:: 34172528
PMCID:: PMC9252855

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV002053718.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces aspartic acid with valine at codon 63 in the ATP binding domain 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer that demonstrated loss of MLH1 and PMS2 proteins via immunohistochemistry analysis (PMID: 23733757; communication with an external laboratory, ClinVar SCV002722481.1), and in an individual affected with unspecified cancer (PMID: 34172528). Several different missense variants at this codon have been classified as pathogenic (ClinVar Variation ID: 89920, 89934, 422297, 957817), supporting that this position is important for protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002722481.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.D63V pathogenic mutation (also known as c.188A>T), located in coding exon 2 of the MLH1 gene, results from an A to T substitution at nucleotide position 188. The aspartic acid at codon 63 is replaced by valine, an amino acid with highly dissimilar properties. This variant was previously reported in a 35 year old male diagnosed with colorectal cancer whose tumor analysis showed microsatellite instability and loss of MLH1 and PMS2 protein by immunohistochemistry (Ward R.L. et al., J. Clin. Oncol. 2013 Jul; 31(20):2554-62). Crystal structural analysis shows that this amino acid residue directly interacts with ATP and is indicated to be part of the ATP binding motif (Ambry internal data). A pathogenic mutation at the same codon, p.D63N, has been reported in a Hungarian family satisfying Amsterdam I criteria for HNPCC/Lynch syndrome. In this family, p.D63N segregated with disease, being detected in the affected proband (CRC at 25y) and his affected father (CRC at 40y) and was absent from 7 cancer-free relatives (Papp J et al. World J. Gastroenterol. 2007 May; 13(19):2727-32). The p.D63N variant has also been identified in multiple individuals with tumors demonstrating loss of MLH1 and PMS2 by immunohistochemistry (Ambry internal data). Another amino acid change at the same codon, p.D63E, has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B. et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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