NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 17, 2023
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:: RCV003279022.2

Allele description [Variation Report for NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs)]

NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs)

HGVS:

NC_000002.12:g.47806464_47806477dup
NG_007111.1:g.28318_28331dup
NG_008397.1:g.104200_104213dup
NM_000179.3:c.3814_3827dupMANE SELECT
NM_001281492.2:c.3424_3437dup
NM_001281493.2:c.2908_2921dup
NM_001281494.2:c.2908_2921dup
NP_000170.1:p.Asp1277fs
NP_000170.1:p.Asp1277fs
NP_001268421.1:p.Asp1147fs
NP_001268422.1:p.Asp975fs
NP_001268423.1:p.Asp975fs
LRG_219t1:c.3814_3827dup
LRG_219:g.28318_28331dup
LRG_219p1:p.Asp1277fs
NC_000002.11:g.48033601_48033602insAGAAAATGAATGTG
NC_000002.11:g.48033603_48033616dup
NM_000179.2:c.3814_3827dup
NM_000179.2:c.3814_3827dupGAAAATGAATGTGA

Protein change:

D1147fs

Links:

dbSNP: rs1558393070

NCBI 1000 Genomes Browser:

rs1558393070

Molecular consequence:

NM_000179.3:c.3814_3827dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3424_3437dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.2908_2921dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.2908_2921dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV004006244	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 17, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004006244

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 17, 2023)

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, SCV004006244.2

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

Description

The c.3814_3827dup14 variant, located in coding exon 9 of the MSH6 gene, results from a duplication of 14 nucleotides at positions 3814 to 3827, causing a translational frameshift with a predicted alternate stop codon (p.D1277Kfs*55). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 84 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted 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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