16-23622984-A-G

Variant names:

• chr16-23622984-A-G
• rs876659645
• NM_024675.4:c.2981T>C

Variant summary

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

The NM_024675.4(PALB2):​c.2981T>C​(p.Phe994Ser) 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:2
• Conservation: PhyloP100: 5.64

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2981T>C	p.Phe994Ser	missense_variant	Exon 9 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2981T>C	p.Phe994Ser	missense_variant	Exon 9 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 18, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F994S variant (also known as c.2981T>C), located in coding exon 9 of the PALB2 gene, results from a T to C substitution at nucleotide position 2981. The phenylalanine at codon 994 is replaced by serine, an amino acid with highly dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6497 samples (12994 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 70000 alleles tested) in our clinical cohort. This amino acid position is well conserved on limited sequence alignment. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.F994S remains unclear. -

Familial cancer of breast Uncertain:1

Jul 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces phenylalanine with serine at codon 994 of the PALB2 protein (p.Phe994Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PALB2-related disease. ClinVar contains an entry for this variant (Variation ID: 232244). 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	Uncertain	0.55
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	.;D
Vest4		0.86
MutPred		0.53		.;Gain of disorder (P = 0.0025);
MVP		0.62
MPC		0.44
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.84
gMVP		0.67

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: rs876659645; hg19: chr16-23634305;