NM_024675.4:c.2453T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_024675.4(PALB2):​c.2453T>C​(p.Phe818Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,134 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. F818L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: -0.569

Publications

7 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 -3 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 35 uncertain in NM_024675.4
BP4
Computational evidence support a benign effect (MetaRNN=0.043617964).
BP6
Variant 16-23629701-A-G is Benign according to our data. Variant chr16-23629701-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 183712.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PALB2NM_024675.4 linkc.2453T>C p.Phe818Ser 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.2453T>C p.Phe818Ser missense_variant Exon 5 of 13 1 NM_024675.4 ENSP00000261584.4 Q86YC2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152240
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000199
AC:
5
AN:
251478
AF XY:
0.0000294
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461894
Hom.:
0
Cov.:
32
AF XY:
0.0000124
AC XY:
9
AN XY:
727248
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000671
AC:
3
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000809
AC:
9
AN:
1112012
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
1
3
4
6
7
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
AF:
0.0000131
AC:
2
AN:
152240
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74382
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41470
American (AMR)
AF:
0.0000655
AC:
1
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5206
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68046
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:3
Mar 30, 2023
Myriad Genetics, Inc.
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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. -

Jan 14, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 818 of the PALB2 protein (p.Phe818Ser). This variant is present in population databases (rs370908330, gnomAD 0.009%). This missense change has been observed in individual(s) with breast and/or pancreatic cancer (PMID: 34326862, 35264596, 35534704). ClinVar contains an entry for this variant (Variation ID: 183712). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Nov 01, 2017
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Hereditary cancer-predisposing syndrome Benign:2
Apr 02, 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. -

Apr 27, 2015
Color Diagnostics, LLC DBA Color Health
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Nov 13, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24485656, 30995915, 35264596, 28779002, 34326862, 34034685) -

Hereditary cancer Benign:1
Feb 27, 2025
Mendelics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
5.0
DANN
Benign
0.63
DEOGEN2
Benign
0.072
T;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.021
N
LIST_S2
Benign
0.55
T;T
M_CAP
Benign
0.0044
T
MetaRNN
Benign
0.044
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.99
.;L
PhyloP100
-0.57
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-1.7
N;N
REVEL
Benign
0.024
Sift
Benign
0.19
T;T
Sift4G
Benign
0.24
T;T
Polyphen
0.0080
.;B
Vest4
0.12
MVP
0.23
MPC
0.089
ClinPred
0.023
T
GERP RS
-4.9
Varity_R
0.11
gMVP
0.23
Mutation Taster
=99/1
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: rs370908330; hg19: chr16-23641022; API