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

Clinical significance:Uncertain significance (Last evaluated: Aug 28, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000791373.3

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_000249.3:c.2210A>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
Protein change:
D379V
Links:
dbSNP: rs267607885
NCBI 1000 Genomes Browser:
rs267607885
Molecular consequence:
  • NM_000249.3:c.2210A>T - missense variant - [Sequence Ontology: SO:0001583]
  • 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:
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000254367Invitaecriteria provided, single submitter
Uncertain significance
(Aug 28, 2020)
germlineclinical testing

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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000254367.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces aspartic acid with valine at codon 737 of the MLH1 protein (p.Asp737Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with colorectal cancer (PMID: 16341550). However, in that individual a pathogenic allele was also identified in MLH1, which suggests that this c.2210A>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 90090). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 30, 2021

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