16-23626378-G-C

Position:

• chr16-23626378-G-C

Variant summary

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

The NM_024675.4(PALB2):​c.2606C>G​(p.Ser869Cys) 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 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S869S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.55

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2606C>G	p.Ser869Cys	missense_variant	7/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2606C>G	p.Ser869Cys	missense_variant	7/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251482 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135914

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: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727244

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: 0.0000187

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

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	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 869 of the PALB2 protein (p.Ser869Cys). This variant is present in population databases (rs779279139, gnomAD 0.004%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26283626, 26315354, 26564480, 30303537). ClinVar contains an entry for this variant (Variation ID: 225855). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 18, 2022	This missense variant replaces serine with cysteine at codon 869 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 been reported in individuals affected with breast or ovarian cancer (PMID: 26283626, 26315354, 26564480, 30303537) and in an unaffected individual (PMID: 32546565), and this variant also has been reported in a breast cancer case-control meta-analysis in 2/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010869). This variant has also been identified in 2/251482 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in a control sample (PMID: 32546565). 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	May 02, 2023	The p.S869C variant (also known as c.2606C>G), located in coding exon 7 of the PALB2 gene, results from a C to G substitution at nucleotide position 2606. The serine at codon 869 is replaced by cysteine, an amino acid with dissimilar properties. This variant has been reported in several cohorts of patients with personal and/or family histories of breast cancer (Thompson ER et al. Breast Cancer Res. 2015; 17(1):111; Decker B et al. J Med Genet, 2017 11;54:732-741; Damiola F et al. Breast Cancer Res. Treat. 2015 Dec; 154(3):463-71; Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This alteration was also observed in 1/3236 cases with invasive epithelial ovarian cancer and in 0/3431 controls (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107). This amino acid position is 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 29, 2016

This variant is denoted PALB2 c.2606C>G at the cDNA level, p.Ser869Cys (S869C) at the protein level, and results in the change of a Serine to a Cysteine (TCC>TGC). This variant was observed in at least two patients with familial breast cancer (Damiola 2015, Thompson 2015). PALB2 Ser869Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Ser869Cys occurs at a position that is not conserved and is located within the WD1 repeat as well as the region of interaction with RAD51, BRCA2 and POLH that is required for interaction with POLH and POLH DNA synthesis stimulation (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PALB2 Ser869Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.5	.;M
MutationTaster	Benign	0.91	D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.61
MutPred		0.30		.;Loss of disorder (P = 0.017);
MVP		0.82
MPC		0.34
ClinPred		0.88	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.26

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: rs779279139; hg19: chr16-23637699; COSMIC: COSV55165901; COSMIC: COSV55165901;