NM_000249.4(MLH1):c.121G>T (p.Asp41Tyr) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 27, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003103288.3

Allele description [Variation Report for NM_000249.4(MLH1):c.121G>T (p.Asp41Tyr)]

NM_000249.4(MLH1):c.121G>T (p.Asp41Tyr)

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.121G>T (p.Asp41Tyr)

HGVS:

NC_000003.12:g.36996623G>T
NG_007109.2:g.8274G>T
NG_008418.1:g.1682C>A
NM_000249.4:c.121G>TMANE SELECT
NM_001167617.3:c.-169G>T
NM_001167618.3:c.-602-1G>T
NM_001167619.3:c.-511G>T
NM_001258271.2:c.121G>T
NM_001258273.2:c.-517+2960G>T
NM_001258274.3:c.-748G>T
NM_001354615.2:c.-506G>T
NM_001354616.2:c.-510-1G>T
NM_001354617.2:c.-602-1G>T
NM_001354618.2:c.-603G>T
NM_001354619.2:c.-603G>T
NM_001354620.2:c.-168-1G>T
NM_001354621.2:c.-696G>T
NM_001354622.2:c.-809G>T
NM_001354623.2:c.-723+2733G>T
NM_001354624.2:c.-706G>T
NM_001354625.2:c.-608-1G>T
NM_001354626.2:c.-705-1G>T
NM_001354627.2:c.-706G>T
NM_001354628.2:c.121G>T
NM_001354629.2:c.121G>T
NM_001354630.2:c.121G>T
NP_000240.1:p.Asp41Tyr
NP_000240.1:p.Asp41Tyr
NP_001245200.1:p.Asp41Tyr
NP_001341557.1:p.Asp41Tyr
NP_001341558.1:p.Asp41Tyr
NP_001341559.1:p.Asp41Tyr
LRG_216t1:c.121G>T
LRG_216:g.8274G>T
LRG_216p1:p.Asp41Tyr
NC_000003.11:g.37038114G>T
NM_000249.3:c.121G>T

Protein change:

D41Y

Molecular consequence:

NM_001167617.3:c.-169G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-511G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-748G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-506G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-603G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-603G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-696G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-809G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-706G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-706G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+2960G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2733G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.121G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.121G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.121G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.121G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.121G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.-602-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354616.2:c.-510-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354617.2:c.-602-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354620.2:c.-168-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354625.2:c.-608-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354626.2:c.-705-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Ncs6p [Saccharomyces cerevisiae S288C]
Ncs6p [Saccharomyces cerevisiae S288C]
gi|50593215|ref|NP_011304.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003252063	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12624141, 19419416, 25060679, 25477341, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003252063

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 27, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Cancer risk in 348 French MSH2 or MLH1 gene carriers.

Parc Y, Boisson C, Thomas G, Olschwang S.

J Med Genet. 2003 Mar;40(3):208-13. No abstract available.

PubMed [citation]

PMID:: 12624141
PMCID:: PMC1735402

Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene.

Tang R, Hsiung C, Wang JY, Lai CH, Chien HT, Chiu LL, Liu CT, Chen HH, Wang HM, Chen SX, Hsieh LL; TCOG HNPCC Consortium..

Clin Genet. 2009 Apr;75(4):334-45. doi: 10.1111/j.1399-0004.2009.01162.x.

PubMed [citation]

PMID:: 19419416

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003252063.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 41 of the MLH1 protein (p.Asp41Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1752818). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function with a positive predictive value of 95%. This variant disrupts the p.Asp41 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12624141, 19419416, 25060679, 25477341; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	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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