NM_024675.4(PALB2):c.3061G>A (p.Gly1021Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 6, 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:: RCV000214675.10

Allele description [Variation Report for NM_024675.4(PALB2):c.3061G>A (p.Gly1021Arg)]

NM_024675.4(PALB2):c.3061G>A (p.Gly1021Arg)

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.3061G>A (p.Gly1021Arg)

HGVS:

NC_000016.10:g.23621414C>T
NG_007406.1:g.24944G>A
NM_024675.4:c.3061G>AMANE SELECT
NP_078951.2:p.Gly1021Arg
NP_078951.2:p.Gly1021Arg
LRG_308t1:c.3061G>A
LRG_308:g.24944G>A
LRG_308p1:p.Gly1021Arg
NC_000016.9:g.23632735C>T
NM_024675.3:c.3061G>A

Protein change:

G1021R

Links:

dbSNP: rs143808171

NCBI 1000 Genomes Browser:

rs143808171

Molecular consequence:

NM_024675.4:c.3061G>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
SCV000274294	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25575445, 31636395 Citation Link,
SCV001735673	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 26, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31636395, 33127389, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000274294

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Oct 6, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001735673

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 26, 2022)

germline

clinical testing

PubMed (3)
[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

Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry.

Nguyen-Dumont T, Hammet F, Mahmoodi M, Tsimiklis H, Teo ZL, Li R, Pope BJ, Terry MB, Buys SS, Daly M, Hopper JL, Winship I, Goldgar DE, Park DJ, Southey MC.

Breast Cancer Res Treat. 2015 Jan;149(2):547-54. doi: 10.1007/s10549-014-3260-8. Epub 2015 Jan 10.

PubMed [citation]

PMID:: 25575445
PMCID:: PMC4542063

Functional characterization of 84 PALB2 variants of uncertain significance.

Wiltshire T, Ducy M, Foo TK, Hu C, Lee KY, Belur Nagaraj A, Rodrigue A, Gomes TT, Simard J, Monteiro ANA, Xia B, Carvalho MA, Masson JY, Couch FJ.

Genet Med. 2020 Mar;22(3):622-632. doi: 10.1038/s41436-019-0682-z. Epub 2019 Oct 21.

PubMed [citation]

PMID:: 31636395
PMCID:: PMC7056643

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000274294.7

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

Description

The p.G1021R variant (also known as c.3061G>A), located in coding exon 10 of the PALB2 gene, results from a G to A substitution at nucleotide position 3061. The glycine at codon 1021 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in 1/1240 probands from the Breast Cancer Family Registry who had previously screened negative for BRCA1 and BRCA2 mutations (Nguyen-Dumont T et al. Breast Cancer Res. Treat., 2015 Jan;149:547-54). This alteration was also found to be functional in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med., 2020 Mar;22:622-632). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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, SCV001735673.2

#	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 glycine with arginine at codon 1021 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). A functional study has shown the mutant protein to exhibit 80% of wild-type activity in a homology-directed repair assay (PMID: 31636395). This variant has been reported in an individual affected with pancreatic cancer (PMID: 33127389). This variant has been identified in 2/251450 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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