16-23635806-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024675.4(PALB2):ā€‹c.740C>Gā€‹(p.Thr247Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000021 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 0.783
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.

BP4
Computational evidence support a benign effect (MetaRNN=0.20431718).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PALB2NM_024675.4 linkc.740C>G p.Thr247Arg missense_variant 4/13 ENST00000261584.9 NP_078951.2 Q86YC2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PALB2ENST00000261584.9 linkc.740C>G p.Thr247Arg missense_variant 4/131 NM_024675.4 ENSP00000261584.4 Q86YC2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251278
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461870
Hom.:
0
Cov.:
33
AF XY:
0.0000234
AC XY:
17
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000261
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:5
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsDec 18, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 247 of the PALB2 protein (p.Thr247Arg). This variant is present in population databases (rs587782658, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 26283626, 26315354). ClinVar contains an entry for this variant (Variation ID: 142706). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Mar 31, 2023This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submittercase-controlCancer Genetics Laboratory, Peter MacCallum Cancer CentreJun 01, 2015- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylAug 23, 2017- -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 19, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 26283626, 26315354, 19369211, 32546565) -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 25, 2016Variant summary: The c.740C>G variant affects a non-conserved nucleotide, resulting in amino acid change from Thr to Arg. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant is not found in 125258 control chromosomes. This variant has been detected in one BrC pt without strong evidence for causality (Thompson_BCR_2015). In addition, one clinical laboratory/reputable database classified this variant as VUS, without evidence to independently evaluate. Because of the lack of clinical information and functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 22, 2019- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 09, 2023This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
12
DANN
Benign
0.97
DEOGEN2
Benign
0.25
T
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.47
FATHMM_MKL
Benign
0.26
N
LIST_S2
Benign
0.52
T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.20
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
L
PrimateAI
Benign
0.24
T
PROVEAN
Uncertain
-2.6
D
REVEL
Benign
0.065
Sift
Uncertain
0.0090
D
Sift4G
Uncertain
0.036
D
Polyphen
0.97
D
Vest4
0.15
MutPred
0.24
Gain of MoRF binding (P = 0.0105);
MVP
0.45
MPC
0.21
ClinPred
0.29
T
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.082
gMVP
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs587782658; hg19: chr16-23647127; API