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NM_000249.4(MLH1):c.2135G>T (p.Trp712Leu) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 16, 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:
RCV003153597.10

Allele description [Variation Report for NM_000249.4(MLH1):c.2135G>T (p.Trp712Leu)]

NM_000249.4(MLH1):c.2135G>T (p.Trp712Leu)

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.2135G>T (p.Trp712Leu)
HGVS:
  • NC_000003.12:g.37050517G>T
  • NG_007109.2:g.62168G>T
  • NM_000249.4:c.2135G>TMANE SELECT
  • NM_001167617.3:c.1841G>T
  • NM_001167618.3:c.1412G>T
  • NM_001167619.3:c.1412G>T
  • NM_001258271.2:c.1928G>T
  • NM_001258273.2:c.1412G>T
  • NM_001258274.3:c.1412G>T
  • NM_001354615.2:c.1412G>T
  • NM_001354616.2:c.1412G>T
  • NM_001354617.2:c.1412G>T
  • NM_001354618.2:c.1412G>T
  • NM_001354619.2:c.1412G>T
  • NM_001354620.2:c.1841G>T
  • NM_001354621.2:c.1112G>T
  • NM_001354622.2:c.1112G>T
  • NM_001354623.2:c.1112G>T
  • NM_001354624.2:c.1061G>T
  • NM_001354625.2:c.1061G>T
  • NM_001354626.2:c.1061G>T
  • NM_001354627.2:c.1061G>T
  • NM_001354628.2:c.2042G>T
  • NM_001354629.2:c.2036G>T
  • NM_001354630.2:c.1970G>T
  • NP_000240.1:p.Trp712Leu
  • NP_000240.1:p.Trp712Leu
  • NP_001161089.1:p.Trp614Leu
  • NP_001161090.1:p.Trp471Leu
  • NP_001161091.1:p.Trp471Leu
  • NP_001245200.1:p.Trp643Leu
  • NP_001245202.1:p.Trp471Leu
  • NP_001245203.1:p.Trp471Leu
  • NP_001341544.1:p.Trp471Leu
  • NP_001341545.1:p.Trp471Leu
  • NP_001341546.1:p.Trp471Leu
  • NP_001341547.1:p.Trp471Leu
  • NP_001341548.1:p.Trp471Leu
  • NP_001341549.1:p.Trp614Leu
  • NP_001341550.1:p.Trp371Leu
  • NP_001341551.1:p.Trp371Leu
  • NP_001341552.1:p.Trp371Leu
  • NP_001341553.1:p.Trp354Leu
  • NP_001341554.1:p.Trp354Leu
  • NP_001341555.1:p.Trp354Leu
  • NP_001341556.1:p.Trp354Leu
  • NP_001341557.1:p.Trp681Leu
  • NP_001341558.1:p.Trp679Leu
  • NP_001341559.1:p.Trp657Leu
  • LRG_216t1:c.2135G>T
  • LRG_216:g.62168G>T
  • LRG_216p1:p.Trp712Leu
  • NC_000003.11:g.37092008G>T
  • NM_000249.3:c.2135G>T
Protein change:
W354L
Links:
dbSNP: rs63750561
NCBI 1000 Genomes Browser:
rs63750561
Molecular consequence:
  • NM_000249.4:c.2135G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.1841G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.1412G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.1412G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.1928G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.1412G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.1412G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.1412G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.1412G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.1412G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.1412G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.1412G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.1841G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354621.2:c.1112G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354622.2:c.1112G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354623.2:c.1112G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354624.2:c.1061G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354625.2:c.1061G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354626.2:c.1061G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354627.2:c.1061G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.2042G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.2036G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.1970G>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
SCV000543663Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 16, 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

Inherited breast cancer predisposition in Asians: multigene panel testing outcomes from Singapore.

Wong ESY, Shekar S, Met-Domestici M, Chan C, Sze M, Yap YS, Rozen SG, Tan MH, Ang P, Ngeow J, Lee ASG.

NPJ Genom Med. 2016;1:15003. doi: 10.1038/npjgenmed.2015.3.

PubMed [citation]
PMID:
29263802
PMCID:
PMC5685290

Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients.

Hu L, Sun J, Li Z, Qu Z, Liu Y, Wan Q, Liu J, Ding X, Zang F, Zhang J, Yao L, Xu Y, Wang Y, Xie Y.

NPJ Breast Cancer. 2022 Apr 21;8(1):52. doi: 10.1038/s41523-022-00417-x.

PubMed [citation]
PMID:
35449176
PMCID:
PMC9023502
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543663.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 712 of the MLH1 protein (p.Trp712Leu). This variant is present in population databases (rs63750561, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 29263802, 35449176). ClinVar contains an entry for this variant (Variation ID: 405437). 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. 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 13, 2024