rs760629975

Positions:

• chr16-23636103-TTTC-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_024675.4(PALB2):​c.440_442del​(p.Arg147del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.27

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_024675.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.440_442del	p.Arg147del	inframe_deletion	4/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.440_442del	p.Arg147del	inframe_deletion	4/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251344 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 371807). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is present in population databases (rs760629975, gnomAD 0.0009%). This variant, c.440_442del, results in the deletion of 1 amino acid(s) of the PALB2 protein (p.Arg147del), but otherwise preserves the integrity of the reading frame. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 22, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 30, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 22, 2021	This variant causes a deletion of 1 amino acid from the PALB2 protein. To our knowledge, functional studies have not been reported for this variant. Over 10 mammalian species have a gap over this amino acid position, suggesting that this variant may be tolerated for PALB2 protein function. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251344 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 16, 2022	The c.440_442delGAA variant (also known as p.R147del) is located in coding exon 4 of the PALB2 gene. This variant results from an in-frame deletion of three nucleotides between nucleotide positions 440 and 442, causing an in-frame deletion of the arginine at codon 147. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 22, 2016

This in-frame deletion of three nucleotides in PALB2 is denoted c.440_442delGAA at the cDNA level and p.Arg147del (R147del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGAA[delGAA]AGAA. This deletion occurs in a region that is not conserved and is located in the region of DNA-binding, and BRCA1 and RAD51 interaction, as well as the region required for oligomerization and focal concentration at DNA damage sites (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider PALB2 Arg147del to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs760629975; hg19: chr16-23647424;