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NM_000249.4(MLH1):c.1732-1G>T AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 17, 2021
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:
RCV002407434.2

Allele description [Variation Report for NM_000249.4(MLH1):c.1732-1G>T]

NM_000249.4(MLH1):c.1732-1G>T

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.1732-1G>T
HGVS:
  • NC_000003.12:g.37047518G>T
  • NG_007109.2:g.59169G>T
  • NM_000249.4:c.1732-1G>TMANE SELECT
  • NM_001167617.3:c.1438-1G>T
  • NM_001167618.3:c.1009-1G>T
  • NM_001167619.3:c.1009-1G>T
  • NM_001258271.2:c.1732-1G>T
  • NM_001258273.2:c.1009-1G>T
  • NM_001258274.3:c.1009-1G>T
  • NM_001354615.2:c.1009-1G>T
  • NM_001354616.2:c.1009-1G>T
  • NM_001354617.2:c.1009-1G>T
  • NM_001354618.2:c.1009-1G>T
  • NM_001354619.2:c.1009-1G>T
  • NM_001354620.2:c.1438-1G>T
  • NM_001354621.2:c.709-1G>T
  • NM_001354622.2:c.709-1G>T
  • NM_001354623.2:c.709-1G>T
  • NM_001354624.2:c.658-1G>T
  • NM_001354625.2:c.658-1G>T
  • NM_001354626.2:c.658-1G>T
  • NM_001354627.2:c.658-1G>T
  • NM_001354628.2:c.1732-1G>T
  • NM_001354629.2:c.1633-1G>T
  • NM_001354630.2:c.1732-999G>T
  • LRG_216t1:c.1732-1G>T
  • LRG_216:g.59169G>T
  • NC_000003.11:g.37089009G>T
  • NM_000249.3:c.1732-1G>T
Molecular consequence:
  • NM_001354630.2:c.1732-999G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.1732-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167617.3:c.1438-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167618.3:c.1009-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167619.3:c.1009-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258271.2:c.1732-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258273.2:c.1009-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258274.3:c.1009-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354615.2:c.1009-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354616.2:c.1009-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354617.2:c.1009-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354618.2:c.1009-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354619.2:c.1009-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354620.2:c.1438-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354621.2:c.709-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354622.2:c.709-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354623.2:c.709-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354624.2:c.658-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354625.2:c.658-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354626.2:c.658-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354627.2:c.658-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354628.2:c.1732-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354629.2:c.1633-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV002715692Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Feb 17, 2021) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

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

Details of each submission

From Ambry Genetics, SCV002715692.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The c.1732-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 16 of the MLH1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, the impacted region is critical for protein function (Ambry internal data). Another alteration impacting the same acceptor site (c.1732-1G>A) has been detected in in HNPCC patients including in a German patient with MSI-H colon cancer showing absent MLH1 staining by IHC; this individual's family met Amsterdam I criteria (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Mueller-Koch Y et al. Gut 2005 Dec;54:1733-40). The c.1732-1G>A mutation was shown to result in in-frame skipping of exon 16, which is required for interaction with PMS2 and conclude it results in functional inactivation of mismatch repair (Castiglia D et al. Genes Chromosomes Cancer 2003 Jun;37:165-75). This variant was not reported in population-based 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: May 1, 2024