rs730881902

Positions:

• chr16-23636025-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The ENST00000261584.9(PALB2):​c.521A>G​(p.Lys174Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K174Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: PALB2 ENST00000261584.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.29

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 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in ENST00000261584.9
• BP4: Computational evidence support a benign effect (MetaRNN=0.077794164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.521A>G	p.Lys174Arg	missense_variant	4/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.521A>G	p.Lys174Arg	missense_variant	4/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251460 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 174 of the PALB2 protein (p.Lys174Arg). This variant is present in population databases (rs730881902, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182783). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 07, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 06, 2021	The p.K174R variant (also known as c.521A>G), located in coding exon 4 of the PALB2 gene, results from an A to G substitution at nucleotide position 521. The lysine at codon 174 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2023	This missense variant replaces lysine with arginine at codon 174 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 not been reported in individuals affected with PALB2-related disorders in the literature. This variant has been identified in 1/251460 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2014

This variant is denoted PALB2 c.521A>G at the cDNA level, p.Lys174Arg (K174R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Lys174Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. PALB2 Lys174Arg occurs at a position that is moderately conserved across species and is located within the DNA binding region and the region involved in interaction with RAD51 and BRCA1 (Teo 2013, UniProt). In addition, in silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PALB2 Lys174Arg is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.036
Sift	Benign	0.095	T
Sift4G	Benign	0.075	T
Polyphen		0.13	B
Vest4		0.23
MutPred		0.098		Loss of ubiquitination at K174 (P = 0.0043);
MVP		0.40
MPC		0.069
ClinPred		0.084	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.091

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs730881902; hg19: chr16-23647346;