U.S. flag

An official website of the United States government

NM_000249.4(MLH1):c.1475C>T (p.Ala492Val) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Oct 27, 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:
RCV000690155.4

Allele description [Variation Report for NM_000249.4(MLH1):c.1475C>T (p.Ala492Val)]

NM_000249.4(MLH1):c.1475C>T (p.Ala492Val)

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.1475C>T (p.Ala492Val)
HGVS:
  • NC_000003.12:g.37028849C>T
  • NG_007109.2:g.40500C>T
  • NM_000249.4:c.1475C>TMANE SELECT
  • NM_001167617.3:c.1181C>T
  • NM_001167618.3:c.752C>T
  • NM_001167619.3:c.752C>T
  • NM_001258271.2:c.1475C>T
  • NM_001258273.2:c.752C>T
  • NM_001258274.3:c.752C>T
  • NM_001354615.2:c.752C>T
  • NM_001354616.2:c.752C>T
  • NM_001354617.2:c.752C>T
  • NM_001354618.2:c.752C>T
  • NM_001354619.2:c.752C>T
  • NM_001354620.2:c.1181C>T
  • NM_001354621.2:c.452C>T
  • NM_001354622.2:c.452C>T
  • NM_001354623.2:c.452C>T
  • NM_001354624.2:c.401C>T
  • NM_001354625.2:c.401C>T
  • NM_001354626.2:c.401C>T
  • NM_001354627.2:c.401C>T
  • NM_001354628.2:c.1475C>T
  • NM_001354629.2:c.1376C>T
  • NM_001354630.2:c.1475C>T
  • NP_000240.1:p.Ala492Val
  • NP_000240.1:p.Ala492Val
  • NP_001161089.1:p.Ala394Val
  • NP_001161090.1:p.Ala251Val
  • NP_001161091.1:p.Ala251Val
  • NP_001245200.1:p.Ala492Val
  • NP_001245202.1:p.Ala251Val
  • NP_001245203.1:p.Ala251Val
  • NP_001341544.1:p.Ala251Val
  • NP_001341545.1:p.Ala251Val
  • NP_001341546.1:p.Ala251Val
  • NP_001341547.1:p.Ala251Val
  • NP_001341548.1:p.Ala251Val
  • NP_001341549.1:p.Ala394Val
  • NP_001341550.1:p.Ala151Val
  • NP_001341551.1:p.Ala151Val
  • NP_001341552.1:p.Ala151Val
  • NP_001341553.1:p.Ala134Val
  • NP_001341554.1:p.Ala134Val
  • NP_001341555.1:p.Ala134Val
  • NP_001341556.1:p.Ala134Val
  • NP_001341557.1:p.Ala492Val
  • NP_001341558.1:p.Ala459Val
  • NP_001341559.1:p.Ala492Val
  • LRG_216t1:c.1475C>T
  • LRG_216:g.40500C>T
  • LRG_216p1:p.Ala492Val
  • NC_000003.11:g.37070340C>T
  • NM_000249.3:c.1475C>T
Protein change:
A134V
Links:
dbSNP: rs1064794826
NCBI 1000 Genomes Browser:
rs1064794826
Molecular consequence:
  • NM_000249.4:c.1475C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.1181C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.752C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.752C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.1475C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.752C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.752C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.752C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.752C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.752C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.752C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.752C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.1181C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354621.2:c.452C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354622.2:c.452C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354623.2:c.452C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354624.2:c.401C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354625.2:c.401C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354626.2:c.401C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354627.2:c.401C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.1475C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.1376C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.1475C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000817833Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Oct 27, 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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000817833.5

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 492 of the MLH1 protein (p.Ala492Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 420973). 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: Feb 28, 2024