NM_024675.4(PALB2):c.3049G>A (p.Ala1017Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 21, 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:: RCV001180325.7

Allele description [Variation Report for NM_024675.4(PALB2):c.3049G>A (p.Ala1017Thr)]

NM_024675.4(PALB2):c.3049G>A (p.Ala1017Thr)

Gene:

PALB2:partner and localizer of BRCA2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.3049G>A (p.Ala1017Thr)

Other names:

NM_024675.4(PALB2):c.3049G>A; p.Ala1017Thr

HGVS:

NC_000016.10:g.23621426C>T
NG_007406.1:g.24932G>A
NM_024675.4:c.3049G>AMANE SELECT
NP_078951.2:p.Ala1017Thr
LRG_308t1:c.3049G>A
LRG_308:g.24932G>A
NC_000016.9:g.23632747C>T
NM_024675.3:c.3049G>A

Protein change:

A1017T

Links:

dbSNP: rs759795184

NCBI 1000 Genomes Browser:

rs759795184

Molecular consequence:

NM_024675.4:c.3049G>A - 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
SCV001345228	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 21, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23977390, 31586400, 25741868
SCV002754109	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23977390, 31586400 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001345228

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 21, 2023)

germline

clinical testing

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

SCV002754109

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 24, 2023)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Prevalence of PALB2 mutations in breast cancer patients in multi-ethnic Asian population in Malaysia and Singapore.

Phuah SY, Lee SY, Kang P, Kang IN, Yoon SY, Thong MK, Hartman M, Sng JH, Yip CH, Taib NA, Teo SH.

PLoS One. 2013;8(8):e73638. doi: 10.1371/journal.pone.0073638.

PubMed [citation]

PMID:: 23977390
PMCID:: PMC3748013

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001345228.2

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

Description

This missense variant replaces alanine with threonine at codon 1017 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported that this variant does not impact PALB2 binding to BRCA2 in a mammalian two-hybrid assay (PMID: 31586400). This variant has been reported in an individual affected with breast cancer (PMID: 23977390). This variant has been identified in 1/251448 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

From Ambry Genetics, SCV002754109.3

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

Description

The p.A1017T variant (also known as c.3049G>A), located in coding exon 10 of the PALB2 gene, results from a G to A substitution at nucleotide position 3049. The alanine at codon 1017 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in in 1/222 Asian women with breast cancer, all of whom had significant family history of breast and other cancers (Phuah SY et al. PLoS ONE, 2013 Aug;8:e73638). In a PARP inhibitor sensitivity assay, this alteration was found to have normal activity. In a BRCA2 binding assay, this alteration was found to have normal activity (Rodrigue A et al. Nucleic Acids Res., 2019 11;47:10662-10677). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, 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

Last Updated: Sep 8, 2024

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