NM_003072.5(SMARCA4):c.1765G>A (p.Ala589Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 19, 2023
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:: RCV002257928.4

Allele description [Variation Report for NM_003072.5(SMARCA4):c.1765G>A (p.Ala589Thr)]

NM_003072.5(SMARCA4):c.1765G>A (p.Ala589Thr)

Gene:

SMARCA4:SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_003072.5(SMARCA4):c.1765G>A (p.Ala589Thr)

HGVS:

NC_000019.10:g.10996497G>A
NG_011556.3:g.40566G>A
NM_001128844.3:c.1765G>A
NM_001128845.2:c.1765G>A
NM_001128846.2:c.1765G>A
NM_001128847.4:c.1765G>A
NM_001128848.2:c.1765G>A
NM_001128849.3:c.1765G>A
NM_001374457.1:c.1765G>A
NM_001387283.1:c.1765G>A
NM_003072.5:c.1765G>AMANE SELECT
NP_001122316.1:p.Ala589Thr
NP_001122317.1:p.Ala589Thr
NP_001122318.1:p.Ala589Thr
NP_001122319.1:p.Ala589Thr
NP_001122320.1:p.Ala589Thr
NP_001122321.1:p.Ala589Thr
NP_001361386.1:p.Ala589Thr
NP_001374212.1:p.Ala589Thr
NP_003063.2:p.Ala589Thr
LRG_878t1:c.1765G>A
LRG_878:g.40566G>A
LRG_878p1:p.Ala589Thr
NC_000019.9:g.11107173G>A
NG_011556.2:g.40576G>A
NM_001128849.1:c.1765G>A
NR_164683.1:n.1941G>A

Protein change:

A589T

Links:

dbSNP: rs765850087

NCBI 1000 Genomes Browser:

rs765850087

Molecular consequence:

NM_001128844.3:c.1765G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128845.2:c.1765G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128846.2:c.1765G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128847.4:c.1765G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128848.2:c.1765G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128849.3:c.1765G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374457.1:c.1765G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001387283.1:c.1765G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003072.5:c.1765G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_164683.1:n.1941G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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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Homologene neighbors for GEO Profiles (Select 82124444) (0)
GEO Profiles
Chromosome neighbors for GEO Profiles (Select 82108376) (21)
GEO Profiles
1392360[uid] (1)
Taxonomy
NADH dehydrogenase subunit 4, partial (mitochondrion) [Malayemys khoratensis]
NADH dehydrogenase subunit 4, partial (mitochondrion) [Malayemys khoratensis]
gi|2805791124|gb|XGZ33438.1|

Protein
essv13117970 (2)
dbVar

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002532792	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Dec 28, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002713358	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 19, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002532792

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Dec 28, 2021)

germline

curation

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

Citation Link,

SCV002713358

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 19, 2023)

germline

clinical testing

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

Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.

Mandelker D, Zhang L, Kemel Y, Stadler ZK, Joseph V, Zehir A, Pradhan N, Arnold A, Walsh MF, Li Y, Balakrishnan AR, Syed A, Prasad M, Nafa K, Carlo MI, Cadoo KA, Sheehan M, Fleischut MH, Salo-Mullen E, Trottier M, Lipkin SM, Lincoln A, et al.

JAMA. 2017 Sep 5;318(9):825-835. doi: 10.1001/jama.2017.11137. Erratum in: JAMA. 2018 Dec 11;320(22):2381. doi: 10.1001/jama.2018.17511.

PubMed [citation]

PMID:: 28873162
PMCID:: PMC5611881

Details of each submission

From Sema4, Sema4, SCV002532792.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	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 Ambry Genetics, SCV002713358.2

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

Description

The p.A589T variant (also known as c.1765G>A), located in coding exon 10 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 1765. The alanine at codon 589 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely.

#	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: May 7, 2024

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