NM_000249.4(MLH1):c.2103+2T>C AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 21, 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:: RCV002424260.2

Allele description [Variation Report for NM_000249.4(MLH1):c.2103+2T>C]

NM_000249.4(MLH1):c.2103+2T>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.2103+2T>C

HGVS:

NC_000003.12:g.37049019T>C
NG_007109.2:g.60670T>C
NM_000249.4:c.2103+2T>CMANE SELECT
NM_001167617.3:c.1809+2T>C
NM_001167618.3:c.1380+2T>C
NM_001167619.3:c.1380+2T>C
NM_001258271.2:c.1896+1336T>C
NM_001258273.2:c.1380+2T>C
NM_001258274.3:c.1380+2T>C
NM_001354615.2:c.1380+2T>C
NM_001354616.2:c.1380+2T>C
NM_001354617.2:c.1380+2T>C
NM_001354618.2:c.1380+2T>C
NM_001354619.2:c.1380+2T>C
NM_001354620.2:c.1809+2T>C
NM_001354621.2:c.1080+2T>C
NM_001354622.2:c.1080+2T>C
NM_001354623.2:c.1080+2T>C
NM_001354624.2:c.1029+2T>C
NM_001354625.2:c.1029+2T>C
NM_001354626.2:c.1029+2T>C
NM_001354627.2:c.1029+2T>C
NM_001354628.2:c.2010+2T>C
NM_001354629.2:c.2004+2T>C
NM_001354630.2:c.1938+2T>C
LRG_216t1:c.2103+2T>C
LRG_216:g.60670T>C
NC_000003.11:g.37090510T>C
NM_000249.3:c.2103+2T>C

Molecular consequence:

NM_001258271.2:c.1896+1336T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.2103+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001167617.3:c.1809+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001167618.3:c.1380+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001167619.3:c.1380+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001258273.2:c.1380+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001258274.3:c.1380+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354615.2:c.1380+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354616.2:c.1380+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354617.2:c.1380+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354618.2:c.1380+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354619.2:c.1380+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354620.2:c.1809+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354621.2:c.1080+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354622.2:c.1080+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354623.2:c.1080+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354624.2:c.1029+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354625.2:c.1029+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354626.2:c.1029+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354627.2:c.1029+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354628.2:c.2010+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354629.2:c.2004+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354630.2:c.1938+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002728374	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Oct 21, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002728374

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Oct 21, 2021)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Ambry Genetics, SCV002728374.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The c.2103+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 18 in the MLH1 gene. This nucleotide position is highly conserved in available vertebrate species. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been identified as somatic in conjunction with a somatic pathogenic MLH1 variant in a MSI-H colon tumor with loss of MLH1/PMS2 expression by immunohistochemistry where MLH1 promotor hypermethylation was negative (Ambry internal data). A similar alteration affecting this same canonical splice site, c.2103+1G>A, has been reported in numerous individuals/families with Lynch syndrome, many of whom had tumor studies showing absent MLH1 protein expression on IHC (Wijnen J et al. Am. J. Hum. Genet. 1996 Feb;58(2):300-7; Berends MJ et al. Int. J. Cancer. 2001 May;92(3):398-403; Wagner A et al. Am. J. Hum. Genet. 2003 May;72(5):1088-100; Overbeek LI et al. Br. J. Cancer. 2007 May;96(10):1605-12; Skeldon SC et al. Eur. Urol. 2013 Feb;63(2):379-85; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36:2823-2835; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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