NM_000179.3(MSH6):c.124C>T (p.Pro42Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 8, 2021
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:: RCV000131942.10

Allele description [Variation Report for NM_000179.3(MSH6):c.124C>T (p.Pro42Ser)]

NM_000179.3(MSH6):c.124C>T (p.Pro42Ser)

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.124C>T (p.Pro42Ser)

HGVS:

NC_000002.12:g.47783357C>T
NG_007111.1:g.5211C>T
NM_000179.3:c.124C>TMANE SELECT
NM_001281492.2:c.124C>T
NM_001281493.2:c.-613C>T
NP_000170.1:p.Pro42Ser
NP_000170.1:p.Pro42Ser
NP_001268421.1:p.Pro42Ser
LRG_219t1:c.124C>T
LRG_219:g.5211C>T
LRG_219p1:p.Pro42Ser
NC_000002.11:g.48010496C>T
NM_000179.2:c.124C>T
p.P42S

Protein change:

P42S

Links:

dbSNP: rs34014629

NCBI 1000 Genomes Browser:

rs34014629

Molecular consequence:

NM_001281493.2:c.-613C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.124C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.124C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000186998	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Likely benign (Oct 29, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22290698, 23621914, 25980754 Citation Link,
SCV000902798	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Sep 30, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002535614	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Oct 8, 2021)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 26437257, 31647837, 25980754, 15872200 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186998

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Likely benign
(Oct 29, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000902798

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Sep 30, 2015)

germline

clinical testing

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

SCV002535614

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Oct 8, 2021)

germline

curation

PubMed (4)
[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	1	not provided	not provided	1	not provided	clinical testing, curation

Citations

PubMed

Classification of mismatch repair gene missense variants with PON-MMR.

Ali H, Olatubosun A, Vihinen M.

Hum Mutat. 2012 Apr;33(4):642-50. doi: 10.1002/humu.22038.

PubMed [citation]

PMID:: 22290698

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

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000186998.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This alteration is classified as likely benign based on a combination of the following: 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	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000902798.1

#	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

From Sema4, Sema4, SCV002535614.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (4)

#	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: Mar 16, 2024

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