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NM_000249.4(MLH1):c.2194A>T (p.Lys732Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 10, 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:
RCV000564805.5

Allele description [Variation Report for NM_000249.4(MLH1):c.2194A>T (p.Lys732Ter)]

NM_000249.4(MLH1):c.2194A>T (p.Lys732Ter)

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.2194A>T (p.Lys732Ter)
HGVS:
  • NC_000003.12:g.37050576A>T
  • NG_007109.2:g.62227A>T
  • NM_000249.4:c.2194A>TMANE SELECT
  • NM_001167617.3:c.1900A>T
  • NM_001167618.3:c.1471A>T
  • NM_001167619.3:c.1471A>T
  • NM_001258271.2:c.1987A>T
  • NM_001258273.2:c.1471A>T
  • NM_001258274.3:c.1471A>T
  • NM_001354615.2:c.1471A>T
  • NM_001354616.2:c.1471A>T
  • NM_001354617.2:c.1471A>T
  • NM_001354618.2:c.1471A>T
  • NM_001354619.2:c.1471A>T
  • NM_001354620.2:c.1900A>T
  • NM_001354621.2:c.1171A>T
  • NM_001354622.2:c.1171A>T
  • NM_001354623.2:c.1171A>T
  • NM_001354624.2:c.1120A>T
  • NM_001354625.2:c.1120A>T
  • NM_001354626.2:c.1120A>T
  • NM_001354627.2:c.1120A>T
  • NM_001354628.2:c.2101A>T
  • NM_001354629.2:c.2095A>T
  • NM_001354630.2:c.2029A>T
  • NP_000240.1:p.Lys732Ter
  • NP_000240.1:p.Lys732Ter
  • NP_001161089.1:p.Lys634Ter
  • NP_001161090.1:p.Lys491Ter
  • NP_001161091.1:p.Lys491Ter
  • NP_001245200.1:p.Lys663Ter
  • NP_001245202.1:p.Lys491Ter
  • NP_001245203.1:p.Lys491Ter
  • NP_001341544.1:p.Lys491Ter
  • NP_001341545.1:p.Lys491Ter
  • NP_001341546.1:p.Lys491Ter
  • NP_001341547.1:p.Lys491Ter
  • NP_001341548.1:p.Lys491Ter
  • NP_001341549.1:p.Lys634Ter
  • NP_001341550.1:p.Lys391Ter
  • NP_001341551.1:p.Lys391Ter
  • NP_001341552.1:p.Lys391Ter
  • NP_001341553.1:p.Lys374Ter
  • NP_001341554.1:p.Lys374Ter
  • NP_001341555.1:p.Lys374Ter
  • NP_001341556.1:p.Lys374Ter
  • NP_001341557.1:p.Lys701Ter
  • NP_001341558.1:p.Lys699Ter
  • NP_001341559.1:p.Lys677Ter
  • LRG_216t1:c.2194A>T
  • LRG_216:g.62227A>T
  • LRG_216p1:p.Lys732Ter
  • NC_000003.11:g.37092067A>T
  • NM_000249.3:c.2194A>T
  • p.Lys732*
Protein change:
K374*
Links:
dbSNP: rs267607906
NCBI 1000 Genomes Browser:
rs267607906
Molecular consequence:
  • NM_000249.4:c.2194A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001167617.3:c.1900A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001167618.3:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001167619.3:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001258271.2:c.1987A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001258273.2:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001258274.3:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354615.2:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354616.2:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354617.2:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354618.2:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354619.2:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354620.2:c.1900A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354621.2:c.1171A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354622.2:c.1171A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354623.2:c.1171A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354624.2:c.1120A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354625.2:c.1120A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354626.2:c.1120A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354627.2:c.1120A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354628.2:c.2101A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354629.2:c.2095A>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354630.2:c.2029A>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000676048Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Apr 10, 2024) 		germlineclinical testing

PubMed (3)
[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

Two novel germline mutations (Y548X and K732X) of the MLH1 gene in Czech patients with hereditary nonpolyposis colorectal cancer.

Hajer J, Kepelová A, Zádorová Z, Kment M.

Hum Mutat. 2000 Aug;16(2):181. No abstract available.

PubMed [citation]
PMID:
10923051

Synchronous gastric and sebaceous cancers, a rare manifestation of MLH1-related Muir-Torre syndrome.

Svec J, Schwarzová L, Janošíková B, Stekrová J, Mandys V, Kment M, Vodička P.

Int J Clin Exp Pathol. 2014;7(8):5196-202.

PubMed [citation]
PMID:
25197397
PMCID:
PMC4152087
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000676048.6

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

Description

The p.K732* pathogenic mutation (also known as c.2194A>T), located in coding exon 19 of the MLH1 gene, results from an A to T substitution at nucleotide position 2194. This changes the amino acid from a lysine to a stop codon within coding exon 19. This alteration occurs at the 3' terminus of theMLH1 gene and is not expected to trigger nonsense-mediated mRNA decay and only impacts the last 25 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been previously reported in a woman of Czech ancestry who was diagnosed with colorectal cancer at age 37 and reportedly met Amsterdam criteria as well as a Caucasian women with endometrial cancer at age 31 with corresponding immunohistochemical (IHC) testing (Hajer J et al. Hum. Mutat. 2000 Aug;16(2):181; Latham A et al. J. Clin. Oncol., 2019 02;37:286-295). This mutation has also been observed in a Caucasian woman with a diagnosis of Muir-Torre syndrome due to metachronous colorectal, endometrial, gastric, and sebaceous carcinomas, all of which showed absence of MLH1 protein expression by IHC analysis (Svec J et al. Int J Clin Exp Pathol. 2014 Jul;7(8):5196-202). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Sep 29, 2024