NM_000179.3(MSH6):c.3244C>T (p.Pro1082Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 19, 2023
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:: RCV000129766.17

Allele description [Variation Report for NM_000179.3(MSH6):c.3244C>T (p.Pro1082Ser)]

NM_000179.3(MSH6):c.3244C>T (p.Pro1082Ser)

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.3244C>T (p.Pro1082Ser)

Other names:

p.P1082S:CCG>TCG

HGVS:

NC_000002.12:g.47803491C>T
NG_007111.1:g.25345C>T
NM_000179.3:c.3244C>TMANE SELECT
NM_001281492.2:c.2854C>T
NM_001281493.2:c.2338C>T
NM_001281494.2:c.2338C>T
NP_000170.1:p.Pro1082Ser
NP_000170.1:p.Pro1082Ser
NP_001268421.1:p.Pro952Ser
NP_001268422.1:p.Pro780Ser
NP_001268423.1:p.Pro780Ser
LRG_219t1:c.3244C>T
LRG_219:g.25345C>T
LRG_219p1:p.Pro1082Ser
NC_000002.11:g.48030630C>T
NM_000179.2:c.3244C>T
p.P1082S

Protein change:

P1082S

Links:

dbSNP: rs186240214

NCBI 1000 Genomes Browser:

rs186240214

Molecular consequence:

NM_000179.3:c.3244C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.2854C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2338C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2338C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184575	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Oct 19, 2023)	germline	clinical testing	Citation Link,
SCV000685370	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 18, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 24100870, 30982232, 31742824, 32980694, 33294277, 33471991, 33588785, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184575

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Oct 19, 2023)

germline

clinical testing

Citation Link,

SCV000685370

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 18, 2023)

germline

clinical testing

PubMed (8)
[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

Molecular and clinical characteristics of MSH6 germline variants detected in colorectal cancer patients.

Terui H, Tachikawa T, Kakuta M, Nishimura Y, Yatsuoka T, Yamaguchi K, Yura K, Akagi K.

Oncol Rep. 2013 Dec;30(6):2909-16. doi: 10.3892/or.2013.2781. Epub 2013 Oct 2.

PubMed [citation]

PMID:: 24100870

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

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000184575.8

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

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, SCV000685370.6

#	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 proline with serine at codon 1082 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with colorectal cancer (PMID: 24100870, 33294277), in an individual affected with urothelial carcinoma (PMID: 33588785), and in at least six individuals suspected of having hereditary breast and ovarian cancer (PMID: 30982232, 31742824). In the colorectal cancer cases, one individual had a pathogenic MLH1 covariant and in a second case the methylation of MLH1 was detected along with the loss of MLH1 and PMS2 proteins by immunohistochemistry (PMID: 24100870, 33294277). This variant also has been detected in a pancreatic cancer case-control study in which it was found in five unaffected control individuals and absent in affected individuals (PMID: 32980694), as well as a breast cancer case-control study where it was found in 11 affected individuals and 12 unaffected control individuals (PMID: 33471991). This variant has been identified in 13/282780 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: Oct 8, 2024

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