NM_024675.4(PALB2):c.3059A>G (p.Gln1020Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 23, 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:: RCV001018358.7

Allele description [Variation Report for NM_024675.4(PALB2):c.3059A>G (p.Gln1020Arg)]

NM_024675.4(PALB2):c.3059A>G (p.Gln1020Arg)

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.3059A>G (p.Gln1020Arg)

HGVS:

NC_000016.10:g.23621416T>C
NG_007406.1:g.24942A>G
NM_024675.4:c.3059A>GMANE SELECT
NP_078951.2:p.Gln1020Arg
NP_078951.2:p.Gln1020Arg
LRG_308t1:c.3059A>G
LRG_308:g.24942A>G
LRG_308p1:p.Gln1020Arg
NC_000016.9:g.23632737T>C
NM_024675.3:c.3059A>G

Protein change:

Q1020R

Links:

dbSNP: rs776221283

NCBI 1000 Genomes Browser:

rs776221283

Molecular consequence:

NM_024675.4:c.3059A>G - 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
SCV001179584	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 23, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002053095	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001179584

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 23, 2023)

germline

clinical testing

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

Citation Link,

SCV002053095

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 3, 2021)

germline

clinical testing

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

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

Prevalence of genetic susceptibility for breast and ovarian cancer in a non-cancer related study population: secondary germline findings from a Swiss single centre cohort.

Kraemer D, Azzarello-Burri S, Steindl K, Boonsawat P, Zweier M, Dedes KJ, Joset P, Fink D, Rauch A.

Swiss Med Wkly. 2019 Aug 12;149:w20092. doi: 10.4414/smw.2019.20092.

PubMed [citation]

PMID:: 31422574

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

Details of each submission

From Ambry Genetics, SCV001179584.5

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

Description

The p.Q1020R variant (also known as c.3059A>G), located in coding exon 10 of the PALB2 gene, results from an A to G substitution at nucleotide position 3059. The glutamine at codon 1020 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in a cohort of Swiss individuals undergoing whole-exome sequencing who had no personal history of cancer (Kraemer D et al. Swiss Med Wkly. 2019 Aug;149:w20092). This amino acid position is well 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

From Color Diagnostics, LLC DBA Color Health, SCV002053095.1

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

Description

This missense variant replaces glutamine with arginine at codon 1020 of the PALB2 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 a breast cancer case-control study in two cases and one unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010790) and in an individual affected with endometrial cancer (PMID: 30093976). This variant has been identified in 4/251452 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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