NM_000249.4(MLH1):c.2210A>T (p.Asp737Val) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 5, 2024
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:: RCV000791373.7

Allele description [Variation Report for NM_000249.4(MLH1):c.2210A>T (p.Asp737Val)]

NM_000249.4(MLH1):c.2210A>T (p.Asp737Val)

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.2210A>T (p.Asp737Val)

Other names:

p.D737V:GAT>GTT

HGVS:

NC_000003.12:g.37050592A>T
NG_007109.2:g.62243A>T
NM_000249.4:c.2210A>TMANE SELECT
NM_001167617.3:c.1916A>T
NM_001167618.3:c.1487A>T
NM_001167619.3:c.1487A>T
NM_001258271.2:c.2003A>T
NM_001258273.2:c.1487A>T
NM_001258274.3:c.1487A>T
NM_001354615.2:c.1487A>T
NM_001354616.2:c.1487A>T
NM_001354617.2:c.1487A>T
NM_001354618.2:c.1487A>T
NM_001354619.2:c.1487A>T
NM_001354620.2:c.1916A>T
NM_001354621.2:c.1187A>T
NM_001354622.2:c.1187A>T
NM_001354623.2:c.1187A>T
NM_001354624.2:c.1136A>T
NM_001354625.2:c.1136A>T
NM_001354626.2:c.1136A>T
NM_001354627.2:c.1136A>T
NM_001354628.2:c.2117A>T
NM_001354629.2:c.2111A>T
NM_001354630.2:c.2045A>T
NP_000240.1:p.Asp737Val
NP_000240.1:p.Asp737Val
NP_001161089.1:p.Asp639Val
NP_001161090.1:p.Asp496Val
NP_001161091.1:p.Asp496Val
NP_001245200.1:p.Asp668Val
NP_001245202.1:p.Asp496Val
NP_001245203.1:p.Asp496Val
NP_001341544.1:p.Asp496Val
NP_001341545.1:p.Asp496Val
NP_001341546.1:p.Asp496Val
NP_001341547.1:p.Asp496Val
NP_001341548.1:p.Asp496Val
NP_001341549.1:p.Asp639Val
NP_001341550.1:p.Asp396Val
NP_001341551.1:p.Asp396Val
NP_001341552.1:p.Asp396Val
NP_001341553.1:p.Asp379Val
NP_001341554.1:p.Asp379Val
NP_001341555.1:p.Asp379Val
NP_001341556.1:p.Asp379Val
NP_001341557.1:p.Asp706Val
NP_001341558.1:p.Asp704Val
NP_001341559.1:p.Asp682Val
LRG_216t1:c.2210A>T
LRG_216:g.62243A>T
LRG_216p1:p.Asp737Val
NC_000003.11:g.37092083A>T
NM_000249.3:c.2210A>T

Protein change:

D379V

Links:

dbSNP: rs267607885

NCBI 1000 Genomes Browser:

rs267607885

Molecular consequence:

NM_000249.4:c.2210A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1916A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.2003A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1916A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1187A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1187A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1187A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1136A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1136A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1136A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1136A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.2117A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.2111A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.2045A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000254367	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 5, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16341550, 31784484, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000254367

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 5, 2024)

germline

clinical testing

PubMed (3)
[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

Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants.

Pagenstecher C, Wehner M, Friedl W, Rahner N, Aretz S, Friedrichs N, Sengteller M, Henn W, Buettner R, Propping P, Mangold E.

Hum Genet. 2006 Mar;119(1-2):9-22. Epub 2005 Dec 8.

PubMed [citation]

PMID:: 16341550

Three-step site-directed mutagenesis screen identifies pathogenic MLH1 variants associated with Lynch syndrome.

Houlleberghs H, Dekker M, Lusseveld J, Pieters W, van Ravesteyn T, Verhoef S, Hofstra RMW, Te Riele H.

J Med Genet. 2020 May;57(5):308-315. doi: 10.1136/jmedgenet-2019-106520. Epub 2019 Nov 29.

PubMed [citation]

PMID:: 31784484

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000254367.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 737 of the MLH1 protein (p.Asp737Val). This variant is present in population databases (rs267607885, gnomAD 0.0009%). This missense change has been observed to co-occur in individuals with a different variant in MLH1 that has been determined to be pathogenic (PMID: 16341550), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 90090). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 31784484). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.

#	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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