rs587782050

chr16-23603544-C-Achr16-23603544-C-Gchr16-23603544-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024675.4(PALB2):c.3476G>T(p.Trp1159Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. W1159R) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.92

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3476G>T	p.Trp1159Leu	missense_variant	13/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3476G>T	p.Trp1159Leu	missense_variant	13/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151910 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151910 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74180

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 05, 2023	The p.W1159L variant (also known as c.3476G>T), located in coding exon 13 of the PALB2 gene, results from a G to T substitution at nucleotide position 3476. The tryptophan at codon 1159 is replaced by leucine, an amino acid with similar properties. In a homology-directed DNA repair (HDR) and PARP inhibitor sensitivity assays, this alteration was found to be functionally normal (Boonen RACM et al. Nat Commun, 2019 11;10:5296). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 20, 2019	This missense variant replaces tryptophan with leucine at codon 1159 of the PALB2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 12, 2023

Variant summary: PALB2 c.3476G>T (p.Trp1159Leu) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251480 control chromosomes (gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3476G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function and found no damaging effect of this variant on homologous recombination or in a PARP inhibitor sensitivity assay (e.g., Boonen_2019). The following publication was ascertained in the context of this evaluation (PMID: 31757951). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 21, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate: protein production, homologous recombination efficiency, and sensitivity to PARP inhibition to proliferation similar to wildtype (Boonen et al., 2019); This variant is associated with the following publications: (PMID: 24485656, 19609323, 20871615, 28152038, 31757951) -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 460996). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 1159 of the PALB2 protein (p.Trp1159Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.093	T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-9.7	D;D
Sift	Uncertain	0.0060	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.75
MutPred		0.60		.;Loss of catalytic residue at W1159 (P = 0.0064);
MVP		0.67
MPC		0.44
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.48

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: rs587782050; hg19: chr16-23614865;