rs1019525144

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024675.4(PALB2):​c.1843C>T​(p.Pro615Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.35
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PALB2NM_024675.4 linkc.1843C>T p.Pro615Ser missense_variant Exon 5 of 13 ENST00000261584.9 NP_078951.2 Q86YC2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PALB2ENST00000261584.9 linkc.1843C>T p.Pro615Ser missense_variant Exon 5 of 13 1 NM_024675.4 ENSP00000261584.4 Q86YC2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461890
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
show subpopulations
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:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3
Dec 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P615S variant (also known as c.1843C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 1843. The proline at codon 615 is replaced by serine, an amino acid with similar properties. This alteration has been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly 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. -

Jul 16, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Nov 20, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Malignant tumor of breast Uncertain:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The PALB2 p.Pro615Ser variant was not identified in the literature nor was it identified in the dbSNP, Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in ClinVar (classified as uncertain significance by Invitae), Clinvitae (classified as uncertain significance by Invitae), databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Pro615 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast Uncertain:1
Apr 13, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline with serine at codon 615 of the PALB2 protein (p.Pro615Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 410120). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.20
T;D
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Benign
0.026
D
MetaRNN
Uncertain
0.63
D;D
MetaSVM
Benign
-0.39
T
MutationAssessor
Benign
1.8
.;L
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-5.9
D;D
REVEL
Uncertain
0.33
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.020
D;D
Polyphen
1.0
.;D
Vest4
0.65
MutPred
0.26
.;Gain of phosphorylation at P615 (P = 0.0488);
MVP
0.87
MPC
0.35
ClinPred
0.99
D
GERP RS
6.2
Varity_R
0.72
gMVP
0.43

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1019525144; hg19: chr16-23641632; API