NM_000179.3(MSH6):c.3556+1del AND Hereditary cancer-predisposing syndrome

Germline classification:: 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:: RCV000491243.4

Allele description [Variation Report for NM_000179.3(MSH6):c.3556+1del]

NM_000179.3(MSH6):c.3556+1del

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3556+1del

HGVS:

NC_000002.12:g.47805028del
NG_007111.1:g.26882del
NG_008397.1:g.105649del
NM_000179.3:c.3556+1delMANE SELECT
NM_001281492.2:c.3166+1del
NM_001281493.2:c.2650+1del
NM_001281494.2:c.2650+1del
NM_001406795.1:c.3652+1del
NM_001406796.1:c.3556+1del
NM_001406797.1:c.3259+1del
NM_001406798.1:c.3382+1del
NM_001406799.1:c.3031+1del
NM_001406800.1:c.3556+1del
NM_001406801.1:c.3259+1del
NM_001406802.1:c.3652+1del
NM_001406803.1:c.2692+1del
NM_001406804.1:c.3478+1del
NM_001406805.1:c.3259+1del
NM_001406806.1:c.3031+1del
NM_001406807.1:c.3031+1del
NM_001406808.1:c.3556+1del
NM_001406809.1:c.3556+1del
NM_001406811.1:c.2650+1del
NM_001406812.1:c.2650+1del
NM_001406813.1:c.3562+1del
NM_001406814.1:c.2650+1del
NM_001406815.1:c.2650+1del
NM_001406816.1:c.2650+1del
NM_001406817.1:c.1990+1del
NM_001406818.1:c.3259+1del
NM_001406819.1:c.3259+1del
NM_001406820.1:c.3259+1del
NM_001406821.1:c.3259+1del
NM_001406822.1:c.3259+1del
NM_001406823.1:c.2650+1del
NM_001406824.1:c.3259+1del
NM_001406825.1:c.3259+1del
NM_001406826.1:c.3388+1del
NM_001406827.1:c.3259+1del
NM_001406828.1:c.3259+1del
NM_001406829.1:c.2650+1del
NM_001406830.1:c.3259+1del
NM_001406831.1:c.337+1del
NM_001406832.1:c.403+1del
NM_001407362.1:c.1501+1del
LRG_219:g.26882del
NC_000002.11:g.48032166del
NC_000002.11:g.48032167del
NM_000179.2:c.3556+1delG

Links:

dbSNP: rs1064793489

NCBI 1000 Genomes Browser:

rs1064793489

Molecular consequence:

NM_000179.3:c.3556+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001281492.2:c.3166+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001281493.2:c.2650+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001281494.2:c.2650+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406795.1:c.3652+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406796.1:c.3556+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406797.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406798.1:c.3382+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406799.1:c.3031+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406800.1:c.3556+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406801.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406802.1:c.3652+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406803.1:c.2692+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406804.1:c.3478+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406805.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406806.1:c.3031+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406807.1:c.3031+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406808.1:c.3556+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406809.1:c.3556+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406811.1:c.2650+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406812.1:c.2650+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406813.1:c.3562+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406814.1:c.2650+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406815.1:c.2650+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406816.1:c.2650+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406817.1:c.1990+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406818.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406819.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406820.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406821.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406822.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406823.1:c.2650+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406824.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406825.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406826.1:c.3388+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406827.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406828.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406829.1:c.2650+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406830.1:c.3259+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406831.1:c.337+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406832.1:c.403+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407362.1:c.1501+1del - 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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LOC121553928 [Coregonus clupeaformis]
LOC121553928 [Coregonus clupeaformis]
Gene ID:121553928

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000580371	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 26, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000580371

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 26, 2022)

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, SCV000580371.7

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

Description

The c.3556+1delG intronic pathogenic mutation, located in intron 6 of the MSH6 gene, results from a deletion of one nucleotide within intron 6 of the MSH6 gene. This variant has been identified in probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability and loss of MSH6 expression by immunohistochemistry (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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 a disease-causing mutation.

#	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: Oct 8, 2024

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