NM_000179.3(MSH6):c.3802-7_3802-4del AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Sep 21, 2023
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:: RCV000491776.7

Allele description [Variation Report for NM_000179.3(MSH6):c.3802-7_3802-4del]

NM_000179.3(MSH6):c.3802-7_3802-4del

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3802-7_3802-4del

HGVS:

NC_000002.12:g.47806441TCTT[1]
NG_007111.1:g.28295TCTT[1]
NG_008397.1:g.104230GAAA[1]
NM_000179.3:c.3802-7_3802-4delMANE SELECT
NM_001281492.2:c.3412-7_3412-4del
NM_001281493.2:c.2896-7_2896-4del
NM_001281494.2:c.2896-7_2896-4del
LRG_219t1:c.3802-7_3802-4del
LRG_219:g.28295TCTT[1]
NC_000002.11:g.48033578_48033581del
NC_000002.11:g.48033580TCTT[1]
NM_000179.2:c.3802-7_3802-4del
NM_000179.2:c.3802-7_3802-4delTCTT

Links:

dbSNP: rs876661171

NCBI 1000 Genomes Browser:

rs876661171

Molecular consequence:

NM_000179.3:c.3802-7_3802-4del - intron variant - [Sequence Ontology: SO:0001627]
NM_001281492.2:c.3412-7_3412-4del - intron variant - [Sequence Ontology: SO:0001627]
NM_001281493.2:c.2896-7_2896-4del - intron variant - [Sequence Ontology: SO:0001627]
NM_001281494.2:c.2896-7_2896-4del - 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
SCV000580092	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Sep 21, 2023)	germline	clinical testing	Citation Link,
SCV000904155	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 5, 2019)	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

SCV000580092

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Sep 21, 2023)

germline

clinical testing

Citation Link,

SCV000904155

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 5, 2019)

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000580092.6

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

Description

The c.3802-7_3802-4delTCTT intronic variant, located in intron 8 of the MSH6 gene, results from a deletion of 4 nucleotides (TCTT) 7 nucleotides upstream of coding exon 9 in the MSH6 gene. This nucleotide region is well conserved in available vertebrate species. This variant segregated with Lynch syndrome-associated disease in four affected members of one family and has been identified in probands whose Lynch syndrome-associated tumor demonstrated loss of MSH6 expression by immunohistochemistry (Ambry internal data). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

From Color Diagnostics, LLC DBA Color Health, SCV000904155.2

#	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: Jul 23, 2024

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