NM_000179.3(MSH6):c.3233T>C (p.Val1078Ala) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 31, 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:: RCV000590417.18

Allele description [Variation Report for NM_000179.3(MSH6):c.3233T>C (p.Val1078Ala)]

NM_000179.3(MSH6):c.3233T>C (p.Val1078Ala)

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.3233T>C (p.Val1078Ala)

HGVS:

NC_000002.12:g.47803480T>C
NG_007111.1:g.25334T>C
NM_000179.3:c.3233T>CMANE SELECT
NM_001281492.2:c.2843T>C
NM_001281493.2:c.2327T>C
NM_001281494.2:c.2327T>C
NP_000170.1:p.Val1078Ala
NP_000170.1:p.Val1078Ala
NP_001268421.1:p.Val948Ala
NP_001268422.1:p.Val776Ala
NP_001268423.1:p.Val776Ala
LRG_219t1:c.3233T>C
LRG_219:g.25334T>C
LRG_219p1:p.Val1078Ala
NC_000002.11:g.48030619T>C
NM_000179.2:c.3233T>C

Protein change:

V1078A

Links:

dbSNP: rs376452612

NCBI 1000 Genomes Browser:

rs376452612

Molecular consequence:

NM_000179.3:c.3233T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.2843T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2327T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2327T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Pohlia cruda voucher MUB 16659 Rps4 (rps4) gene, partial cds; and rps4-trnS intergenic spacer, complete sequence; chloroplast
gi|323370859|gb|JF277326.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000568925	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jan 31, 2024)	germline	clinical testing	Citation Link,
SCV000601564	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Dec 9, 2022)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 33471991, 32659497, 23621914, 28767289, 26467025
SCV001473035	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Mar 9, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000568925

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jan 31, 2024)

germline

clinical testing

Citation Link,

SCV000601564

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Dec 9, 2022)

unknown

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001473035

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Mar 9, 2020)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

Association of Germline Variants in Human DNA Damage Repair Genes and Response to Adjuvant Chemotherapy in Resected Pancreatic Ductal Adenocarcinoma.

Hu H, Zhu Y, Pu N, Burkhart RA, Burns W, Laheru D, Zheng L, He J, Goggins MG, Yu J.

J Am Coll Surg. 2020 Nov;231(5):527-535.e14. doi: 10.1016/j.jamcollsurg.2020.06.019. Epub 2020 Jul 11.

PubMed [citation]

PMID:: 32659497

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000568925.6

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with pancreatic or breast cancer (PMID: 32659497, 33471991, 28767289); This variant is associated with the following publications: (PMID: 24728327, 23621914, 28767289, 32659497, 17531815, 21120944, 33471991)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601564.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The frequency of this variant in the general population, 0.000035 (4/113696 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with pancreatic ductal adenocarcinoma (PDAC) (PMIDs: 32659497 (2020), 28767289 (2017)) and in individuals with breast cancer in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001473035.1

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

Description

The MSH6 c.3233T>C; p.Val1078Ala variant (rs376452612) is reported in the literature in an individual with pancreatic cancer and a family history of prostate cancer (Shindo 2017). This variant is also reported in the ClinVar database (Variation ID: 134855). It is found in the general population with a low overall allele frequency of 0.002% (5/251376 alleles) in the Genome Aggregation Database. The valine at codon 1078 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390.

#	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 26, 2024

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