NM_000179.3(MSH6):c.43C>T (p.Pro15Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 14, 2024
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:: RCV000164343.11

Allele description [Variation Report for NM_000179.3(MSH6):c.43C>T (p.Pro15Ser)]

NM_000179.3(MSH6):c.43C>T (p.Pro15Ser)

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.43C>T (p.Pro15Ser)

HGVS:

NC_000002.12:g.47783276C>T
NG_007111.1:g.5130C>T
NM_000179.3:c.43C>TMANE SELECT
NM_001281492.2:c.43C>T
NM_001281493.2:c.-694C>T
NP_000170.1:p.Pro15Ser
NP_000170.1:p.Pro15Ser
NP_001268421.1:p.Pro15Ser
LRG_219t1:c.43C>T
LRG_219:g.5130C>T
LRG_219p1:p.Pro15Ser
NC_000002.11:g.48010415C>T
NM_000179.2:c.43C>T
p.P15S

Protein change:

P15S

Links:

dbSNP: rs776745497

NCBI 1000 Genomes Browser:

rs776745497

Molecular consequence:

NM_001281493.2:c.-694C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.43C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.43C>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

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SRP061949 (9)
SRA
PREDICTED: Mus musculus R3H domain containing 1 (R3hdm1), transcript variant X22...
PREDICTED: Mus musculus R3H domain containing 1 (R3hdm1), transcript variant X22, mRNA
gi|1907068344|ref|XM_030253186.2|

Nucleotide
Chain C, Prunin
Chain C, Prunin
gi|266618563|pdb|3FZ3|C

Protein
Chain B, Prunin
Chain B, Prunin
gi|266618562|pdb|3FZ3|B

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000214976	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 14, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28944238, 30982232, 35449176 Citation Link,
SCV000690442	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 30, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28944238, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000214976

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 14, 2024)

germline

clinical testing

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

Citation Link,

SCV000690442

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 30, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Germline mutation landscape of Chinese patients with familial breast/ovarian cancer in a panel of 22 susceptibility genes.

Wang J, Li W, Shi Y, Huang Y, Sun T, Tang L, Lu Q, Lei Q, Liao N, Jin F, Li H, Huang T, Qian J, Pang D, Wang S, Fan P, Wu X, Lin Y, Qin H, Xu B.

Cancer Med. 2019 May;8(5):2074-2084. doi: 10.1002/cam4.2093. Epub 2019 Apr 13.

PubMed [citation]

PMID:: 30982232
PMCID:: PMC6536923

Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients.

Hu L, Sun J, Li Z, Qu Z, Liu Y, Wan Q, Liu J, Ding X, Zang F, Zhang J, Yao L, Xu Y, Wang Y, Xie Y.

NPJ Breast Cancer. 2022 Apr 21;8(1):52. doi: 10.1038/s41523-022-00417-x.

PubMed [citation]

PMID:: 35449176
PMCID:: PMC9023502

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000214976.7

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

Description

The p.P15S variant (also known as c.43C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 43. The proline at codon 15 is replaced by serine, an amino acid with similar properties. In one study, this alteration was identified in 1/1231 individuals diagnosed with colorectal cancer, who had targeted sequencing of thirty-six known or putative colorectal cancer susceptibility genes (DeRycke MS et al. Mol Genet Genomic Med. 2017 Sep;5:553-569). This alteration has also been identified in multiple individuals diagnosed with breast cancer (Wang J et al. Cancer Med, 2019 May;8:2074-2084; Hu L et al. NPJ Breast Cancer, 2022 Apr;8:52). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, 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, SCV000690442.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces proline with serine at codon 15 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 been reported in an individual affected with colorectal cancer (PMID: 28944238). This variant has been identified in 6/244720 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

Last Updated: Sep 29, 2024

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