NM_000179.3(MSH6):c.3646+1G>A AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 26, 2022
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:: RCV001974193.5

Allele description [Variation Report for NM_000179.3(MSH6):c.3646+1G>A]

NM_000179.3(MSH6):c.3646+1G>A

Gene:

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3646+1G>A

HGVS:

NC_000002.12:g.47805708G>A
NG_007111.1:g.27562G>A
NG_008397.1:g.104968C>T
NM_000179.3:c.3646+1G>AMANE SELECT
NM_001281492.2:c.3256+1G>A
NM_001281493.2:c.2740+1G>A
NM_001281494.2:c.2740+1G>A
NM_001406795.1:c.3742+1G>A
NM_001406796.1:c.3646+1G>A
NM_001406797.1:c.3349+1G>A
NM_001406798.1:c.3472+1G>A
NM_001406799.1:c.3121+1G>A
NM_001406800.1:c.3646+1G>A
NM_001406801.1:c.3349+1G>A
NM_001406802.1:c.3742+1G>A
NM_001406803.1:c.2782+1G>A
NM_001406804.1:c.3568+1G>A
NM_001406805.1:c.3349+1G>A
NM_001406806.1:c.3121+1G>A
NM_001406807.1:c.3121+1G>A
NM_001406808.1:c.3646+1G>A
NM_001406809.1:c.3646+1G>A
NM_001406811.1:c.2740+1G>A
NM_001406812.1:c.2740+1G>A
NM_001406813.1:c.3652+1G>A
NM_001406814.1:c.2740+1G>A
NM_001406815.1:c.2740+1G>A
NM_001406816.1:c.2740+1G>A
NM_001406817.1:c.2080+1G>A
NM_001406818.1:c.3349+1G>A
NM_001406819.1:c.3349+1G>A
NM_001406820.1:c.3349+1G>A
NM_001406821.1:c.3349+1G>A
NM_001406822.1:c.3349+1G>A
NM_001406823.1:c.2740+1G>A
NM_001406824.1:c.3349+1G>A
NM_001406825.1:c.3349+1G>A
NM_001406826.1:c.3478+1G>A
NM_001406827.1:c.3349+1G>A
NM_001406828.1:c.3349+1G>A
NM_001406829.1:c.2740+1G>A
NM_001406830.1:c.3349+1G>A
NM_001406831.1:c.427+1G>A
NM_001406832.1:c.493+1G>A
NM_001407362.1:c.1591+1G>A
LRG_219:g.27562G>A
NC_000002.11:g.48032847G>A

Links:

dbSNP: rs1553332772

NCBI 1000 Genomes Browser:

rs1553332772

Molecular consequence:

NM_000179.3:c.3646+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001281492.2:c.3256+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001281493.2:c.2740+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001281494.2:c.2740+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406795.1:c.3742+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406796.1:c.3646+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406797.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406798.1:c.3472+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406799.1:c.3121+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406800.1:c.3646+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406801.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406802.1:c.3742+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406803.1:c.2782+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406804.1:c.3568+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406805.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406806.1:c.3121+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406807.1:c.3121+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406808.1:c.3646+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406809.1:c.3646+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406811.1:c.2740+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406812.1:c.2740+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406813.1:c.3652+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406814.1:c.2740+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406815.1:c.2740+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406816.1:c.2740+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406817.1:c.2080+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406818.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406819.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406820.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406821.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406822.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406823.1:c.2740+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406824.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406825.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406826.1:c.3478+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406827.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406828.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406829.1:c.2740+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406830.1:c.3349+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406831.1:c.427+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406832.1:c.493+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407362.1:c.1591+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002260475	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 26, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 18269114, 24362816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002260475

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 26, 2022)

germline

clinical testing

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

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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts.

Devlin LA, Graham CA, Price JH, Morrison PJ.

Ulster Med J. 2008 Jan;77(1):25-30.

PubMed [citation]

PMID:: 18269114
PMCID:: PMC2397009

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV002260475.3

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 7 of the MSH6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816).

#	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: Feb 28, 2024

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