16-23630101-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024675.4(PALB2):ā€‹c.2053A>Cā€‹(p.Lys685Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: 0.0330
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06735155).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PALB2NM_024675.4 linkuse as main transcriptc.2053A>C p.Lys685Gln missense_variant 5/13 ENST00000261584.9 NP_078951.2 Q86YC2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PALB2ENST00000261584.9 linkuse as main transcriptc.2053A>C p.Lys685Gln missense_variant 5/131 NM_024675.4 ENSP00000261584.4 Q86YC2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251460
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461886
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
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

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 07, 2016This variant is denoted PALB2 c.2053A>C at the cDNA level, p.Lys685Gln (K685Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Lys685Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. PALB2 Lys685Gln occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PALB2 Lys685Gln is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, no assertion criteria providedcurationLeiden Open Variation DatabaseOct 10, 2018Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthDec 20, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 29, 2022The p.K685Q variant (also known as c.2053A>C), located in coding exon 5 of the PALB2 gene, results from an A to C substitution at nucleotide position 2053. The lysine at codon 685 is replaced by glutamine, an amino acid with similar properties. This alteration was not observed in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00018 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is not 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. -
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 685 of the PALB2 protein (p.Lys685Gln). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 245754). 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
0.10
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
3.6
DANN
Benign
0.68
DEOGEN2
Benign
0.026
T;T
Eigen
Benign
-0.95
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.048
N
LIST_S2
Benign
0.56
T;T
M_CAP
Benign
0.0073
T
MetaRNN
Benign
0.067
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.77
.;N
PrimateAI
Benign
0.22
T
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.014
Sift
Benign
0.21
T;T
Sift4G
Benign
0.23
T;T
Polyphen
0.23
.;B
Vest4
0.13
MutPred
0.17
.;Loss of methylation at K685 (P = 0.0049);
MVP
0.35
MPC
0.069
ClinPred
0.049
T
GERP RS
-0.71
Varity_R
0.056
gMVP
0.099

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: rs876660397; hg19: chr16-23641422; API