rs863224785

Variant names:

• chr16-23608005-A-G
• rs863224785
• NM_024675.4:c.3209T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024675.4(PALB2):​c.3209T>C​(p.Leu1070Pro) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 6.17

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]

ENSG00000261723 (HGNC:58305):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3209T>C	p.Leu1070Pro	missense_variant	Exon 12 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3209T>C	p.Leu1070Pro	missense_variant	Exon 12 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:1

Feb 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Uncertain:1

Aug 12, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Nov 07, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in an individual with breast cancer and a family history of pancreatic cancer in published literature (PMID: 34399810); 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; This variant is associated with the following publications: (PMID: 31636395, 33169439, 32185139, 33195396, 32209438, 33964450, 19609323, 20871615, 24485656, 31757951, 34399810) -

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L1070P variant (also known as c.3209T>C), located in coding exon 12 of the PALB2 gene, results from a T to C substitution at nucleotide position 3209. The leucine at codon 1070 is replaced by proline, an amino acid with similar properties. This alteration was identified in an individual diagnosed with breast cancer (Murali K et al. Hered Cancer Clin Pract, 2021 Aug;19:33). This alteration was found to be functionally abnormal in multiple homology-directed DNA repair (HDR) assays (Boonen RACM et al. Nat Commun, 2019 11;10:5296; Wiltshire T et al. Genet. Med., 2020 03;22:622-632; Brnich SE et al. J Mol Diagn, 2021 Jul;23:847-864). In addition, in a PARP inhibitor sensitivity assay, this alteration was found to be functionally inconclusive (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 deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial cancer of breast Uncertain:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1070 of the PALB2 protein (p.Leu1070Pro). This variant is not present in population databases (gnomAD no frequency). 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: 216752). 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. Experimental studies have shown that this missense change affects PALB2 function (PMID: 31636395, 31757951, 33964450). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	2.0	.;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.93
MutPred		0.63		.;Loss of sheet (P = 0.0043);
MVP		0.74
MPC		0.42
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.96
gMVP		0.87

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: rs863224785; hg19: chr16-23619326; COSMIC: COSV55162866;