chr16-23630457-C-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024675.4(PALB2):​c.1697G>C​(p.Arg566Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R566H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: -1.89

Publications

8 publications found
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]
PALB2 Gene-Disease associations (from GenCC):
  • hereditary breast carcinoma
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
  • Fanconi anemia complementation group N
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
  • pancreatic cancer, susceptibility to, 3
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • familial ovarian cancer
    Inheritance: AD Classification: MODERATE Submitted by: ClinGen
  • Fanconi anemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary nonpolyposis colon cancer
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.08345267).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PALB2NM_024675.4 linkc.1697G>C p.Arg566Pro 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.1697G>C p.Arg566Pro missense_variant Exon 5 of 13 1 NM_024675.4 ENSP00000261584.4 Q86YC2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000122
AC:
3
AN:
246172
AF XY:
0.00000749
show subpopulations
Gnomad AFR exome
AF:
0.0000633
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000181
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1459534
Hom.:
0
Cov.:
32
AF XY:
0.00000551
AC XY:
4
AN XY:
726052
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33434
American (AMR)
AF:
0.00
AC:
0
AN:
44560
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26084
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39676
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85954
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53154
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000450
AC:
5
AN:
1110594
Other (OTH)
AF:
0.00
AC:
0
AN:
60312
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 01, 2021
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jun 19, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The PALB2 c.1697G>C (p.Arg566Pro) variant has not been reported in individuals with PALB2-related conditions in the published literature. The frequency of this variant in the general population, 0.000012 (3/246172 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Mar 28, 2024
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Feb 15, 2021
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces arginine with proline at codon 566 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/246172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 Uncertain:1
May 03, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial cancer of breast Uncertain:1
Dec 18, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 566 of the PALB2 protein (p.Arg566Pro). This variant is present in population databases (rs144617793, gnomAD 0.007%). 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: 140894). 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 not expected to disrupt PALB2 protein function with a negative 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
0.20
DANN
Benign
0.77
DEOGEN2
Benign
0.015
T;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.048
N
LIST_S2
Benign
0.41
T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.083
T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.90
.;L
PhyloP100
-1.9
PrimateAI
Benign
0.20
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.043
Sift
Benign
0.14
T;T
Sift4G
Benign
0.26
T;T
Polyphen
0.61
.;P
Vest4
0.27
MutPred
0.26
.;Loss of MoRF binding (P = 0.003);
MVP
0.20
MPC
0.098
ClinPred
0.054
T
GERP RS
-3.6
Varity_R
0.13
gMVP
0.085
Mutation Taster
=97/3
polymorphism

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

Other links and lift over

dbSNP: rs144617793; hg19: chr16-23641778; API