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NM_000249.4(MLH1):c.43G>A (p.Val15Met) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 20, 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:
RCV000527289.6

Allele description [Variation Report for NM_000249.4(MLH1):c.43G>A (p.Val15Met)]

NM_000249.4(MLH1):c.43G>A (p.Val15Met)

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.43G>A (p.Val15Met)
HGVS:
  • NC_000003.12:g.36993590G>A
  • NG_007109.2:g.5241G>A
  • NG_008418.1:g.4715C>T
  • NM_000249.4:c.43G>AMANE SELECT
  • NM_001167617.3:c.-474G>A
  • NM_001167618.3:c.-903G>A
  • NM_001167619.3:c.-816G>A
  • NM_001258271.2:c.43G>A
  • NM_001258273.2:c.-590G>A
  • NM_001258274.3:c.-1053G>A
  • NM_001354615.2:c.-584G>A
  • NM_001354616.2:c.-584G>A
  • NM_001354617.2:c.-676G>A
  • NM_001354618.2:c.-908G>A
  • NM_001354619.2:c.-1032G>A
  • NM_001354620.2:c.-242G>A
  • NM_001354621.2:c.-1001G>A
  • NM_001354622.2:c.-1114G>A
  • NM_001354623.2:c.-1023G>A
  • NM_001354624.2:c.-784G>A
  • NM_001354625.2:c.-682G>A
  • NM_001354626.2:c.-779G>A
  • NM_001354627.2:c.-1011G>A
  • NM_001354628.2:c.43G>A
  • NM_001354629.2:c.43G>A
  • NM_001354630.2:c.43G>A
  • NP_000240.1:p.Val15Met
  • NP_000240.1:p.Val15Met
  • NP_001245200.1:p.Val15Met
  • NP_001341557.1:p.Val15Met
  • NP_001341558.1:p.Val15Met
  • NP_001341559.1:p.Val15Met
  • LRG_216t1:c.43G>A
  • LRG_216:g.5241G>A
  • LRG_216p1:p.Val15Met
  • NC_000003.11:g.37035081G>A
  • NM_000249.3:c.43G>A
Protein change:
V15M
Links:
dbSNP: rs876660301
NCBI 1000 Genomes Browser:
rs876660301
Molecular consequence:
  • NM_001167617.3:c.-474G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-903G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-816G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-590G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-1053G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-584G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-584G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-676G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-908G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-1032G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-242G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-1001G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-1114G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-1023G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-784G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-682G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-779G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-1011G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000249.4:c.43G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.43G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.43G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.43G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.43G>A - 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
SCV000625163Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Mar 20, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000625163.5

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

Description

This missense change has been observed in individual(s) with clinical features of MLH1-related conditions (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. 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. ClinVar contains an entry for this variant (Variation ID: 233273). This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in MLH1 in at least one individual (Invitae), which suggests that this variant may not be disease-causing. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 15 of the MLH1 protein (p.Val15Met).

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

Last Updated: Sep 29, 2024