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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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000254367Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 5, 2024) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024