NM_000179.3(MSH6):c.3283C>T (p.Arg1095Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Dec 7, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000115413.23

Allele description [Variation Report for NM_000179.3(MSH6):c.3283C>T (p.Arg1095Cys)]

NM_000179.3(MSH6):c.3283C>T (p.Arg1095Cys)

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.3283C>T (p.Arg1095Cys)

Other names:

p.R1095C:CGC>TGC

HGVS:

NC_000002.12:g.47803530C>T
NG_007111.1:g.25384C>T
NM_000179.3:c.3283C>TMANE SELECT
NM_001281492.2:c.2893C>T
NM_001281493.2:c.2377C>T
NM_001281494.2:c.2377C>T
NP_000170.1:p.Arg1095Cys
NP_000170.1:p.Arg1095Cys
NP_001268421.1:p.Arg965Cys
NP_001268422.1:p.Arg793Cys
NP_001268423.1:p.Arg793Cys
LRG_219t1:c.3283C>T
LRG_219:g.25384C>T
LRG_219p1:p.Arg1095Cys
NC_000002.11:g.48030669C>T
NM_000179.2:c.3283C>T
p.R1095C

Protein change:

R1095C

Links:

dbSNP: rs376243329

NCBI 1000 Genomes Browser:

rs376243329

Molecular consequence:

NM_000179.3:c.3283C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.2893C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2377C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2377C>T - 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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Homo sapiens genomic DNA, chromosome 11 clone:RP11-159N11, complete sequence
Homo sapiens genomic DNA, chromosome 11 clone:RP11-159N11, complete sequence
gi|40736960|dbj|AP002840.3|

Nucleotide
Synaptoporin [Mus musculus]
Synaptoporin [Mus musculus]
gi|20071498|gb|AAH26512.1|

Protein
Danio rerio genomic clone DKEY-183P4, genomic survey sequence
Danio rerio genomic clone DKEY-183P4, genomic survey sequence
gi|28012399|emb|BX180591.1|

Nucleotide
BX329716 Homo sapiens NEUROBLASTOMA COT 25-NORMALIZED Homo sapiens cDNA clone CS...
BX329716 Homo sapiens NEUROBLASTOMA COT 25-NORMALIZED Homo sapiens cDNA clone CS0DC027YF10 3-PRIME, mRNA sequence
gi|46271714|gnl|dbEST|22350683|emb| 716.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000172721	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Feb 18, 2020)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12522549, 23621914, 24728327, 28531214, 30093976, 30159786, 31386297, 31391288 Citation Link,
SCV000685382	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 7, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12522549, 26845104, 30093976, 30159786, 31391288, 32980694, 33471991, 25741868
SCV002528003	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jan 10, 2022)	germline	curation	PubMed (10) [See all records that cite these PMIDs] 30159786, 30093976, 31386297, 26845104, 31391288, 29044863, 24448499, 24728327, 33471991, 28531214 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000172721

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Feb 18, 2020)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV000685382

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 7, 2022)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV002528003

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Jan 10, 2022)

germline

curation

PubMed (10)
[See all records that cite these PMIDs]

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

CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein.

Terui H, Akagi K, Kawame H, Yura K.

J Biomed Sci. 2013 Apr 28;20:25. doi: 10.1186/1423-0127-20-25.

PubMed [citation]

PMID:: 23621914
PMCID:: PMC3651391

Two mismatch repair gene mutations found in a colon cancer patient--which one is pathogenic?

Kariola R, Otway R, Lönnqvist KE, Raevaara TE, Macrae F, Vos YJ, Kohonen-Corish M, Hofstra RM, Nyström-Lahti M.

Hum Genet. 2003 Feb;112(2):105-9. Epub 2002 Nov 21.

PubMed [citation]

PMID:: 12522549

See all PubMed Citations (14)

Details of each submission

From Ambry Genetics, SCV000172721.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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, SCV000685382.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces arginine with cysteine at codon 1095 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with Lynch syndrome-associated cancers (PMID: 12522549, 26845104, 30093976, 31391288), breast cancer (PMID: 30159786) and an unspecified cancer (PMID: 31391288). This variant also has been observed in a pancreatic cancer case-control study in multiple unaffected individuals and absent in affected individuals (PMID: 32980694), and in a breast cancer case-control study in both affected and unaffected individuals (PMID: 33471991). This variant has been identified in 23/282860 chromosomes 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, SCV002528003.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (10)

#	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: Aug 4, 2024

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