NM_000249.4(MLH1):c.453+1G>T AND Hereditary cancer-predisposing syndrome

Clinical significance:Likely pathogenic (Last evaluated: Feb 25, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001022649.2

Allele description [Variation Report for NM_000249.4(MLH1):c.453+1G>T]

NM_000249.4(MLH1):c.453+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.453+1G>T
HGVS:
  • NC_000003.12:g.37007064G>T
  • NG_007109.2:g.18715G>T
  • NM_000249.4:c.453+1G>TMANE SELECT
  • NM_001167617.3:c.159+1G>T
  • NM_001167618.3:c.-271+1G>T
  • NM_001167619.3:c.-179+1G>T
  • NM_001258271.2:c.453+1G>T
  • NM_001258273.2:c.-271+1G>T
  • NM_001258274.3:c.-271+1G>T
  • NM_001354615.2:c.-179+1G>T
  • NM_001354616.2:c.-179+1G>T
  • NM_001354617.2:c.-271+1G>T
  • NM_001354618.2:c.-271+1G>T
  • NM_001354619.2:c.-271+1G>T
  • NM_001354620.2:c.159+1G>T
  • NM_001354621.2:c.-364+1G>T
  • NM_001354622.2:c.-477+1G>T
  • NM_001354623.2:c.-477+1G>T
  • NM_001354624.2:c.-374+1G>T
  • NM_001354625.2:c.-282+1G>T
  • NM_001354626.2:c.-374+1G>T
  • NM_001354627.2:c.-374+1G>T
  • NM_001354628.2:c.453+1G>T
  • NM_001354629.2:c.354+1G>T
  • NM_001354630.2:c.453+1G>T
  • LRG_216t1:c.453+1G>T
  • LRG_216:g.18715G>T
  • NC_000003.11:g.37048555G>T
  • NM_000249.3:c.453+1G>T
Links:
dbSNP: rs267607750
NCBI 1000 Genomes Browser:
rs267607750
Molecular consequence:
  • NM_000249.4:c.453+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167617.3:c.159+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167618.3:c.-271+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167619.3:c.-179+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258271.2:c.453+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258273.2:c.-271+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258274.3:c.-271+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354615.2:c.-179+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354616.2:c.-179+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354617.2:c.-271+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354618.2:c.-271+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354619.2:c.-271+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354620.2:c.159+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354621.2:c.-364+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354622.2:c.-477+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354623.2:c.-477+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354624.2:c.-374+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354625.2:c.-282+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354626.2:c.-374+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354627.2:c.-374+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354628.2:c.453+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354629.2:c.354+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354630.2:c.453+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
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
SCV001184409Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Feb 25, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Mismatch repair gene mutations in Chinese HNPCC patients.

Sheng JQ, Fu L, Sun ZQ, Huang JS, Han M, Mu H, Zhang H, Zhang YZ, Zhang MZ, Li AQ, Wu ZT, Han Y, Li SR.

Cytogenet Genome Res. 2008;122(1):22-7. doi: 10.1159/000151312. Epub 2008 Oct 14.

PubMed [citation]
PMID:
18931482

RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.

Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, Morris Q, Barash Y, Krainer AR, Jojic N, Scherer SW, Blencowe BJ, Frey BJ.

Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.

PubMed [citation]
PMID:
25525159
PMCID:
PMC4362528
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV001184409.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)

Description

The c.453+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 5 of the MLH1 gene. This alteration has been reported in one Chinese family meeting Lynch syndrome criteria and is predicted to induce a large splicing event (Sheng JQ et al. Cytogenet. Genome Res., 2008 Oct;122:22-7; Xiong HY et al. Science, 2015 Jan;347:1254806). This alteration was also seen in a Chinese individual with jejunum, colon, renal, and pancreatic cancer all before age 50. Family history included a mother that passed from rectal cancer at age 45 (Zhang JX et al. World J. Gastroenterol., 2015 Apr;21:4136-49). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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 likely pathogenic.

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

Last Updated: Nov 27, 2021

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