rs786203248

chr16-23623083-A-Gchr16-23623083-A-T

Variant summary

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

The NM_024675.4(PALB2):c.2882T>C(p.Leu961Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. L961M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.01

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]

(HGNC:):

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, 0.789

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.2882T>C	p.Leu961Pro	missense_variant	9/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.2882T>C	p.Leu961Pro	missense_variant	9/13	1	NM_024675.4	P1
	ENST00000561764.1	n.420-817A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2021	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 have shown that this variant affects PALB2 protein function (PMID: 31757951). This variant has not been reported in the literature in individuals with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 186824). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 961 of the PALB2 protein (p.Leu961Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2023

The p.L961P variant (also known as c.2882T>C), located in coding exon 9 of the PALB2 gene, results from a T to C substitution at nucleotide position 2882. The leucine at codon 961 is replaced by proline, an amino acid with similar properties. This variant was found to be functionally abnormal in a homology-directed DNA repair (HDR) assay, a PARP inhibitor assay, and a RAD51 foci assay (Boonen RACM et al. Nat Commun, 2019 11;10:5296). This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358). This amino acid position is not well 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.043	T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.1	D;D
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.043	D;D
Polyphen		1.0	.;D
Vest4		0.89
MutPred		0.49		.;Loss of stability (P = 0.0097);
MVP		0.66
MPC		0.42
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.93
gMVP		0.74

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: rs786203248; hg19: chr16-23634404;