NM_000249.4(MLH1):c.306+4A>G AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jul 26, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000130593.13

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 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
SCV000185466	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 26, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18561205, 26898890, 31159747, 32634176 Citation Link,
SCV000684817	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26898890, 32634176, 25741868
SCV000822023	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185466

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 26, 2024)

germline

clinical testing

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

Citation Link,

SCV000684817

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 28, 2023)

germline

clinical testing

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

SCV000822023

GeneKor MSA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 1, 2018)

germline

clinical testing

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

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

Citations

PubMed

A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects.

Tournier I, Vezain M, Martins A, Charbonnier F, Baert-Desurmont S, Olschwang S, Wang Q, Buisine MP, Soret J, Tazi J, Frébourg T, Tosi M.

Hum Mutat. 2008 Dec;29(12):1412-24. doi: 10.1002/humu.20796.

PubMed [citation]

PMID:: 18561205

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

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000185466.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The c.306+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 3 in the MLH1 gene. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This variant was also observed in 1/287 patients with hereditary breast and/or ovarian cancer (Caminsky NG et al. Hum Mutat, 2016 07;37:640-52). Furthermore, this variant was identified in 1/199 endometrial cancer patients (Singh AK et al. PLoS One, 2020 Jul;15(7):e0235613). In a functional RNA study, this variant was associated with in-frame exon 3 skipping and activation of a cryptic donor site in exon 3; however, splicing was tested using a mini gene assay and patient RNA was not analyzed (Tournier I et al. Hum. Mutat. 2008 Dec;29:1412-24). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). However, this alteration has been detected in many probands who do not have a personal or family history that is consistent with or suggestive of hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome and one of these individuals was diagnosed with microsatellite stable colorectal cancer that demonstrated normal mismatch repair protein expression by immunohistochemistry (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV000684817.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant causes an A to G nucleotide substitution at the +4 position of intron 3 of the MLH1 gene. To our knowledge, functional studies have not been reported for this variant. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. This variant has been reported in individuals affected with endometrial cancer and breast cancer (PMID: 26898890, 32634176). This variant has been identified in 3/251334 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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

From GeneKor MSA, SCV000822023.1

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

#	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: Jan 19, 2025

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