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NM_000249.4(MLH1):c.1039-3C>G AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 10, 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:
RCV002390389.2

Allele description [Variation Report for NM_000249.4(MLH1):c.1039-3C>G]

NM_000249.4(MLH1):c.1039-3C>G

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.1039-3C>G
HGVS:
  • NC_000003.12:g.37025634C>G
  • NG_007109.2:g.37285C>G
  • NM_000249.4:c.1039-3C>GMANE SELECT
  • NM_001167617.3:c.745-3C>G
  • NM_001167618.3:c.316-3C>G
  • NM_001167619.3:c.316-3C>G
  • NM_001258271.2:c.1039-3C>G
  • NM_001258273.2:c.316-3C>G
  • NM_001258274.3:c.316-3C>G
  • NM_001354615.2:c.316-3C>G
  • NM_001354616.2:c.316-3C>G
  • NM_001354617.2:c.316-3C>G
  • NM_001354618.2:c.316-3C>G
  • NM_001354619.2:c.316-3C>G
  • NM_001354620.2:c.745-3C>G
  • NM_001354621.2:c.16-3C>G
  • NM_001354622.2:c.16-3C>G
  • NM_001354623.2:c.16-3C>G
  • NM_001354624.2:c.-36-3C>G
  • NM_001354625.2:c.-36-3C>G
  • NM_001354626.2:c.-36-3C>G
  • NM_001354627.2:c.-36-3C>G
  • NM_001354628.2:c.1039-3C>G
  • NM_001354629.2:c.940-3C>G
  • NM_001354630.2:c.1039-3C>G
  • LRG_216t1:c.1039-3C>G
  • LRG_216:g.37285C>G
  • NC_000003.11:g.37067125C>G
  • NM_000249.3:c.1039-3C>G
Links:
dbSNP: rs730881737
NCBI 1000 Genomes Browser:
rs730881737
Molecular consequence:
  • NM_000249.4:c.1039-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001167617.3:c.745-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001167618.3:c.316-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001167619.3:c.316-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258271.2:c.1039-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258273.2:c.316-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258274.3:c.316-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354615.2:c.316-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354616.2:c.316-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354617.2:c.316-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354618.2:c.316-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354619.2:c.316-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354620.2:c.745-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354621.2:c.16-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354622.2:c.16-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354623.2:c.16-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354624.2:c.-36-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354625.2:c.-36-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354626.2:c.-36-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354627.2:c.-36-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354628.2:c.1039-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354629.2:c.940-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354630.2:c.1039-3C>G - intron variant - [Sequence Ontology: SO:0001627]

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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002700646Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Likely pathogenic
(Dec 10, 2021)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From Ambry Genetics, SCV002700646.2

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

Description

The c.1039-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 12 in the MLH1 gene. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MLH1/PMS2 expression by immunohistochemistry (Ambry internal data). This nucleotide position is well conserved through mammals. 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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: Jun 9, 2024