NM_000249.4(MLH1):c.1990-1G>C AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Sep 27, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000772614.3

Allele description [Variation Report for NM_000249.4(MLH1):c.1990-1G>C]

NM_000249.4(MLH1):c.1990-1G>C

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.1990-1G>C
HGVS:
  • NC_000003.12:g.37048903G>C
  • NG_007109.2:g.60554G>C
  • NM_000249.3:c.1990-1G>C
  • NM_000249.4:c.1990-1G>CMANE SELECT
  • NM_001167617.3:c.1696-1G>C
  • NM_001167618.3:c.1267-1G>C
  • NM_001167619.3:c.1267-1G>C
  • NM_001258271.2:c.1896+1220G>C
  • NM_001258273.2:c.1267-1G>C
  • NM_001258274.3:c.1267-1G>C
  • NM_001354615.2:c.1267-1G>C
  • NM_001354616.2:c.1267-1G>C
  • NM_001354617.2:c.1267-1G>C
  • NM_001354618.2:c.1267-1G>C
  • NM_001354619.2:c.1267-1G>C
  • NM_001354620.2:c.1696-1G>C
  • NM_001354621.2:c.967-1G>C
  • NM_001354622.2:c.967-1G>C
  • NM_001354623.2:c.967-1G>C
  • NM_001354624.2:c.916-1G>C
  • NM_001354625.2:c.916-1G>C
  • NM_001354626.2:c.916-1G>C
  • NM_001354627.2:c.916-1G>C
  • NM_001354628.2:c.1897-1G>C
  • NM_001354629.2:c.1891-1G>C
  • NM_001354630.2:c.1825-1G>C
  • LRG_216t1:c.1990-1G>C
  • LRG_216:g.60554G>C
  • NC_000003.11:g.37090394G>C
Links:
dbSNP: rs267607884
NCBI 1000 Genomes Browser:
rs267607884
Molecular consequence:
  • NM_001258271.2:c.1896+1220G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.3:c.1990-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_000249.4:c.1990-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167617.3:c.1696-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167618.3:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167619.3:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258273.2:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258274.3:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354615.2:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354616.2:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354617.2:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354618.2:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354619.2:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354620.2:c.1696-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354621.2:c.967-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354622.2:c.967-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354623.2:c.967-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354624.2:c.916-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354625.2:c.916-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354626.2:c.916-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354627.2:c.916-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354628.2:c.1897-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354629.2:c.1891-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354630.2:c.1825-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
Observations:
1

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000905795Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Sep 27, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001174619Ambry Geneticscriteria provided, single submitter
Pathogenic
(Feb 7, 2018)
germlineclinical testing

Citation Link

Description

This variant causes a G>C nucleotide substitution at the -1 position of intron 17 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to disrupt the PMS2/MLH3/PMS1 interacting domain. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice acceptor site (c.1990-1G>A, c.1990-1G>T) are considered to be disease-causing (ClinVar variation ID: 89985, 89986), suggesting that the reference sequence at this splice site is important for normal RNA splicing. Based on the available evidence, this variant is classified as Likely Pathogenic.

SCV000905795

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Color Health, Inc, SCV000905795.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Ambry Genetics, SCV001174619.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.1990-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 18 of the MLH1 gene. <span style="background-color:initial">A similar alteration at the same nucleotide position, <span style="background-color:initial">c.1990-1G>A, has been reported in a family meeting Amsterdam criteria and was shown to cause exon skipping (<span style="background-color:initial">G<span style="background-color:initial">odino<span style="background-color:initial"> J et al. Hum. Mutat. 2001 Dec;18(6):549; Thompson BA et al. Hum. Mutat. 2013 Jan;34(1):200-9). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Oct 30, 2021

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