NM_000249.4(MLH1):c.1897-2A>G AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: May 15, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000249.4(MLH1):c.1897-2A>G]


MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000003.12:g.37048515A>G
  • NG_007109.2:g.60166A>G
  • NM_000249.4:c.1897-2A>GMANE SELECT
  • NM_001167617.3:c.1603-2A>G
  • NM_001167618.3:c.1174-2A>G
  • NM_001167619.3:c.1174-2A>G
  • NM_001258271.2:c.1896+832A>G
  • NM_001258273.2:c.1174-2A>G
  • NM_001258274.3:c.1174-2A>G
  • NM_001354615.2:c.1174-2A>G
  • NM_001354616.2:c.1174-2A>G
  • NM_001354617.2:c.1174-2A>G
  • NM_001354618.2:c.1174-2A>G
  • NM_001354619.2:c.1174-2A>G
  • NM_001354620.2:c.1603-2A>G
  • NM_001354621.2:c.874-2A>G
  • NM_001354622.2:c.874-2A>G
  • NM_001354623.2:c.874-2A>G
  • NM_001354624.2:c.823-2A>G
  • NM_001354625.2:c.823-2A>G
  • NM_001354626.2:c.823-2A>G
  • NM_001354627.2:c.823-2A>G
  • NM_001354628.2:c.1897-389A>G
  • NM_001354629.2:c.1798-2A>G
  • NM_001354630.2:c.1732-2A>G
  • LRG_216t1:c.1897-2A>G
  • LRG_216:g.60166A>G
  • NC_000003.11:g.37090006A>G
  • NM_000249.3:c.1897-2A>G
dbSNP: rs267607871
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001258271.2:c.1896+832A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354628.2:c.1897-389A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.1897-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167617.3:c.1603-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167618.3:c.1174-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167619.3:c.1174-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258273.2:c.1174-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258274.3:c.1174-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354615.2:c.1174-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354616.2:c.1174-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354617.2:c.1174-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354618.2:c.1174-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354619.2:c.1174-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354620.2:c.1603-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354621.2:c.874-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354622.2:c.874-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354623.2:c.874-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354624.2:c.823-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354625.2:c.823-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354626.2:c.823-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354627.2:c.823-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354629.2:c.1798-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354630.2:c.1732-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000669547Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Nov 14, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000908649Color Health, Inccriteria provided, single submitter
Likely pathogenic
(May 15, 2020)
germlineclinical testing

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


This variant causes an A to G nucleotide substitution at the -2 position of intron 16 of the MLH1 gene. Splice site prediction tools suggest that this variant would impair splicing at the intron 16 splice acceptor site, which is expected to produce an absent or non-functional protein with disruption in the PMS2/MLH3/PMS1-interacting domain. This variant has been reported in two related individuals affected with Lynch syndrome (PMID: 15345113) and in individuals affected with colorectal cancer (PMID: 27978560, 28135145). This variant has also been identified in 1/251356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant has been classified as Likely Pathogenic.


Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Mutation analysis of hMSH2 and hMLH1 in colorectal cancer patients in India.

Rajkumar T, Soumittra N, Pandey D, Nancy KN, Mahajan V, Majhi U.

Genet Test. 2004 Summer;8(2):157-62.

PubMed [citation]

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.

Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, Ukaegbu CI, Brais LK, McNamara PG, Mayer RJ, Schrag D, Meyerhardt JA, Ng K, Kidd J, Singh N, Hartman AR, Wenstrup RJ, Syngal S.

J Clin Oncol. 2017 Apr 1;35(10):1086-1095. doi: 10.1200/JCO.2016.71.0012. Epub 2017 Jan 30.

PubMed [citation]
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000669547.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)


The c.1897-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 17 in the MLH1 gene. This alteration has been identified in two probands with early-onset colorectal cancer, one of whom had a MSI-high tumor and met Bethesda criteria for Lynch syndrome; however, the colon tumor of the second proband was reported to be mismatch repair (MMR) proficient demonstrating microsatellite stability and/or normal immunohistochemistry (Rajkumar T et al. Genet. Test. 2004 ;8(2):157-62; Pearlman R et al. JAMA Oncol. 2017 Apr;3(4):464-471). This variant was also reported in an individual from a cohort of unselected colorectal cancer patients undergoing multigene panel testing (Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35:1086-1095). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated this alteration does not result in significant abnormal splicing compared to non-carrier control samples (Ambry internal data). Of note, this alteration is also designated as IVS16-2A>G in the published literature. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

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

From Color Health, Inc, SCV000908649.2

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

Last Updated: Nov 27, 2021

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