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NM_000249.4(MLH1):c.62C>T (p.Ala21Val) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jul 14, 2022
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:
RCV002362709.3

Allele description [Variation Report for NM_000249.4(MLH1):c.62C>T (p.Ala21Val)]

NM_000249.4(MLH1):c.62C>T (p.Ala21Val)

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.62C>T (p.Ala21Val)
HGVS:
  • NC_000003.12:g.36993609C>T
  • NG_007109.2:g.5260C>T
  • NG_008418.1:g.4696G>A
  • NM_000249.4:c.62C>TMANE SELECT
  • NM_001167617.3:c.-455C>T
  • NM_001167618.3:c.-884C>T
  • NM_001167619.3:c.-797C>T
  • NM_001258271.2:c.62C>T
  • NM_001258273.2:c.-571C>T
  • NM_001258274.3:c.-1034C>T
  • NM_001354615.2:c.-565C>T
  • NM_001354616.2:c.-565C>T
  • NM_001354617.2:c.-657C>T
  • NM_001354618.2:c.-889C>T
  • NM_001354619.2:c.-1013C>T
  • NM_001354620.2:c.-223C>T
  • NM_001354621.2:c.-982C>T
  • NM_001354622.2:c.-1095C>T
  • NM_001354623.2:c.-1004C>T
  • NM_001354624.2:c.-765C>T
  • NM_001354625.2:c.-663C>T
  • NM_001354626.2:c.-760C>T
  • NM_001354627.2:c.-992C>T
  • NM_001354628.2:c.62C>T
  • NM_001354629.2:c.62C>T
  • NM_001354630.2:c.62C>T
  • NP_000240.1:p.Ala21Val
  • NP_000240.1:p.Ala21Val
  • NP_001245200.1:p.Ala21Val
  • NP_001341557.1:p.Ala21Val
  • NP_001341558.1:p.Ala21Val
  • NP_001341559.1:p.Ala21Val
  • LRG_216t1:c.62C>T
  • LRG_216:g.5260C>T
  • LRG_216p1:p.Ala21Val
  • NC_000003.11:g.37035100C>T
  • NM_000249.3:c.62C>T
  • P40692:p.Ala21Val
Protein change:
A21V
Links:
UniProtKB: P40692#VAR_043384; dbSNP: rs63750706
NCBI 1000 Genomes Browser:
rs63750706
Molecular consequence:
  • NM_001167617.3:c.-455C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-884C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-797C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-571C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-1034C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-565C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-565C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-657C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-889C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-1013C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-223C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-982C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-1095C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-1004C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-765C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-663C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-760C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-992C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000249.4:c.62C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.62C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.62C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.62C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.62C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002657222Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Jul 14, 2022) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden.

Cederquist K, Emanuelsson M, Göransson I, Holinski-Feder E, Müller-Koch Y, Golovleva I, Grönberg H.

Int J Cancer. 2004 Apr 10;109(3):370-6. Erratum in: Int J Cancer. 2005 Jul 20;115(6):1011.

PubMed [citation]
PMID:
14961575

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.

Lagerstedt-Robinson K, Rohlin A, Aravidis C, Melin B, Nordling M, Stenmark-Askmalm M, Lindblom A, Nilbert M.

Oncol Rep. 2016 Nov;36(5):2823-2835. doi: 10.3892/or.2016.5060. Epub 2016 Sep 1.

PubMed [citation]
PMID:
27601186
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002657222.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The p.A21V variant (also known as c.62C>T), located in coding exon 1 of the MLH1 gene, results from a C to T substitution at nucleotide position 62. The alanine at codon 21 is replaced by valine, an amino acid with similar properties. This variant has been reported in multiple Lynch syndrome/HNPCC families to date with microsatellite unstable (MSI-H) tumors and absent MLH1 and/or PMS2 on immunohistochemistry (Cederquist K et al. Int. J. Cancer, 2004 Apr;109:370-6; Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835; Alqahtani M et al. Fam. Cancer, 2018 Apr;17:197-203; Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16). In an in vitro complementation assay, this variant was determined to be functionally deficient (Drost M et al. Genet Med, 2019 07;21:1486-1496). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Sep 16, 2024