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NM_000249.4(MLH1):c.306+4A>G AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 1, 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:
RCV000524290.8

Allele description [Variation Report for NM_000249.4(MLH1):c.306+4A>G]

NM_000249.4(MLH1):c.306+4A>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.306+4A>G
HGVS:
  • NC_000003.12:g.37001057A>G
  • NG_007109.2:g.12708A>G
  • NM_000249.4:c.306+4A>GMANE SELECT
  • NM_001167617.3:c.12+9A>G
  • NM_001167618.3:c.-418+4A>G
  • NM_001167619.3:c.-326+4A>G
  • NM_001258271.2:c.306+4A>G
  • NM_001258273.2:c.-418+4A>G
  • NM_001258274.3:c.-418+4A>G
  • NM_001354615.2:c.-326+9A>G
  • NM_001354616.2:c.-326+4A>G
  • NM_001354617.2:c.-418+4A>G
  • NM_001354618.2:c.-418+4A>G
  • NM_001354619.2:c.-418+4A>G
  • NM_001354620.2:c.12+9A>G
  • NM_001354621.2:c.-511+4A>G
  • NM_001354622.2:c.-624+4A>G
  • NM_001354623.2:c.-624+4A>G
  • NM_001354624.2:c.-521+4A>G
  • NM_001354625.2:c.-429+9A>G
  • NM_001354626.2:c.-521+4A>G
  • NM_001354627.2:c.-521+4A>G
  • NM_001354628.2:c.306+4A>G
  • NM_001354629.2:c.208-3344A>G
  • NM_001354630.2:c.306+4A>G
  • LRG_216t1:c.306+4A>G
  • LRG_216:g.12708A>G
  • NC_000003.11:g.37042548A>G
  • NM_000249.3:c.306+4A>G
Links:
dbSNP: rs267607733
NCBI 1000 Genomes Browser:
rs267607733
Molecular consequence:
  • NM_000249.4:c.306+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001167617.3:c.12+9A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001167618.3:c.-418+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001167619.3:c.-326+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258271.2:c.306+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258273.2:c.-418+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258274.3:c.-418+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354615.2:c.-326+9A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354616.2:c.-326+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354617.2:c.-418+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354618.2:c.-418+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354619.2:c.-418+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354620.2:c.12+9A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354621.2:c.-511+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354622.2:c.-624+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354623.2:c.-624+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354624.2:c.-521+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354625.2:c.-429+9A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354626.2:c.-521+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354627.2:c.-521+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354628.2:c.306+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354629.2:c.208-3344A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354630.2:c.306+4A>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000543612Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 1, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.

Tsaousis GN, Papadopoulou E, Apessos A, Agiannitopoulos K, Pepe G, Kampouri S, Diamantopoulos N, Floros T, Iosifidou R, Katopodi O, Koumarianou A, Markopoulos C, Papazisis K, Venizelos V, Xanthakis I, Xepapadakis G, Banu E, Eniu DT, Negru S, Stanculeanu DL, Ungureanu A, Ozmen V, et al.

BMC Cancer. 2019 Jun 3;19(1):535. doi: 10.1186/s12885-019-5756-4.

PubMed [citation]
PMID:
31159747
PMCID:
PMC6547505

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543612.8

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

Description

This sequence change falls in intron 3 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs267607733, gnomAD 0.003%). This variant has been observed in individual(s) with breast and/or ovarian cancer, endometiral cancer, and/or clinical features of Lynch syndrome (PMID: 18561205, 31159747). ClinVar contains an entry for this variant (Variation ID: 90147). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 18561205; Invitae). 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: Sep 29, 2024