NM_000179.3(MSH6):c.3974A>G (p.Lys1325Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 5, 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:: RCV000219276.13

Allele description [Variation Report for NM_000179.3(MSH6):c.3974A>G (p.Lys1325Arg)]

NM_000179.3(MSH6):c.3974A>G (p.Lys1325Arg)

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.3974A>G (p.Lys1325Arg)

HGVS:

NC_000002.12:g.47806624A>G
NG_007111.1:g.28478A>G
NG_008397.1:g.104052T>C
NM_000179.3:c.3974A>GMANE SELECT
NM_001281492.2:c.3584A>G
NM_001281493.2:c.3068A>G
NM_001281494.2:c.3068A>G
NP_000170.1:p.Lys1325Arg
NP_000170.1:p.Lys1325Arg
NP_001268421.1:p.Lys1195Arg
NP_001268422.1:p.Lys1023Arg
NP_001268423.1:p.Lys1023Arg
LRG_219t1:c.3974A>G
LRG_219:g.28478A>G
LRG_219p1:p.Lys1325Arg
NC_000002.11:g.48033763A>G
NM_000179.2:c.3974A>G

Protein change:

K1023R

Links:

dbSNP: rs876658189

NCBI 1000 Genomes Browser:

rs876658189

Molecular consequence:

NM_000179.3:c.3974A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3584A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.3068A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.3068A>G - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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PREDICTED: Homo sapiens laminin subunit beta 4 (LAMB4), transcript variant X2, m...
PREDICTED: Homo sapiens laminin subunit beta 4 (LAMB4), transcript variant X2, mRNA
gi|2462613134|ref|XM_054357629.1|

Nucleotide
RecName: Full=Laminin subunit beta-4; AltName: Full=Laminin beta-1-related prote...
RecName: Full=Laminin subunit beta-4; AltName: Full=Laminin beta-1-related protein; Flags: Precursor
gi|162416049|sp|A4D0S4.1|LAMB4_HUMA

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000273110	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 19, 2023)	germline	clinical testing	Citation Link,
SCV000903217	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 5, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002536303	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Dec 26, 2021)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000273110

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 19, 2023)

germline

clinical testing

Citation Link,

SCV000903217

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 5, 2023)

germline

clinical testing

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

SCV002536303

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Dec 26, 2021)

germline

curation

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, curation

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, SCV000273110.8

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

Description

The p.K1325R variant (also known as c.3974A>G), located in coding exon 9 of the MSH6 gene, results from an A to G substitution at nucleotide position 3974. The lysine at codon 1325 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited 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, SCV000903217.4

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

Description

This missense variant replaces lysine with arginine at codon 1325 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has not been identified 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 Sema4, Sema4, SCV002536303.1

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

#	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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