16-23635536-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024675.4(PALB2):​c.1010T>C​(p.Leu337Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,613,480 control chromosomes in the GnomAD database, including 322 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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: 𝑓 0.015 ( 37 hom., cov: 32)
Exomes 𝑓: 0.019 ( 285 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:27O:1

Conservation

PhyloP100: 0.842
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 Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0021042824).
BP6
Variant 16-23635536-A-G is Benign according to our data. Variant chr16-23635536-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126582.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=15, Likely_benign=2, not_provided=1}. Variant chr16-23635536-A-G is described in Lovd as [Benign]. Variant chr16-23635536-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0146 (2216/152220) while in subpopulation NFE AF= 0.0211 (1437/68006). AF 95% confidence interval is 0.0202. There are 37 homozygotes in gnomad4. There are 1102 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 37 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PALB2NM_024675.4 linkc.1010T>C p.Leu337Ser missense_variant Exon 4 of 13 ENST00000261584.9 NP_078951.2 Q86YC2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PALB2ENST00000261584.9 linkc.1010T>C p.Leu337Ser missense_variant Exon 4 of 13 1 NM_024675.4 ENSP00000261584.4 Q86YC2

Frequencies

GnomAD3 genomes
AF:
0.0146
AC:
2215
AN:
152102
Hom.:
37
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00396
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00950
Gnomad ASJ
AF:
0.00346
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00352
Gnomad FIN
AF:
0.0399
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0211
Gnomad OTH
AF:
0.00812
GnomAD3 exomes
AF:
0.0147
AC:
3679
AN:
250924
Hom.:
45
AF XY:
0.0143
AC XY:
1937
AN XY:
135676
show subpopulations
Gnomad AFR exome
AF:
0.00314
Gnomad AMR exome
AF:
0.00658
Gnomad ASJ exome
AF:
0.00487
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00373
Gnomad FIN exome
AF:
0.0456
Gnomad NFE exome
AF:
0.0192
Gnomad OTH exome
AF:
0.0126
GnomAD4 exome
AF:
0.0191
AC:
27915
AN:
1461260
Hom.:
285
Cov.:
32
AF XY:
0.0186
AC XY:
13508
AN XY:
726942
show subpopulations
Gnomad4 AFR exome
AF:
0.00276
Gnomad4 AMR exome
AF:
0.00639
Gnomad4 ASJ exome
AF:
0.00536
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00354
Gnomad4 FIN exome
AF:
0.0448
Gnomad4 NFE exome
AF:
0.0212
Gnomad4 OTH exome
AF:
0.0178
GnomAD4 genome
AF:
0.0146
AC:
2216
AN:
152220
Hom.:
37
Cov.:
32
AF XY:
0.0148
AC XY:
1102
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.00395
Gnomad4 AMR
AF:
0.00949
Gnomad4 ASJ
AF:
0.00346
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00353
Gnomad4 FIN
AF:
0.0399
Gnomad4 NFE
AF:
0.0211
Gnomad4 OTH
AF:
0.00803
Alfa
AF:
0.0163
Hom.:
44
Bravo
AF:
0.0110
TwinsUK
AF:
0.0259
AC:
96
ALSPAC
AF:
0.0166
AC:
64
ESP6500AA
AF:
0.00364
AC:
16
ESP6500EA
AF:
0.0197
AC:
169
ExAC
AF:
0.0142
AC:
1729
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.0164
EpiControl
AF:
0.0184

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:27Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:7Other:1
-
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 11, 2013
GeneDx
Significance: 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 criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 29, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Hereditary cancer-predisposing syndrome Benign:7
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 12, 2021
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

May 23, 2018
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 12, 2018
True Health Diagnostics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 03, 2015
Vantari Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 18, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

Jan 02, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:6
Aug 07, 2019
Leiden Open Variation Database
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Maximiliano Zeballos, Melissa DeRycke. -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PALB2: BP4, BS1, BS2 -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 23, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1Benign:4
May 10, 2023
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Mar 23, 2016
Counsyl
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 06, 2014
Pathway Genomics
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 01, 2015
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: case-control

- -

Breast and/or ovarian cancer Benign:1
Jan 14, 2020
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Fanconi anemia complementation group N Benign:1
Mar 06, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

The PALB2 p.Leu337Ser variant was identified in 190 of 11072 proband chromosomes (frequency: 0.0175) from individuals or families with CMM, breast, ovarian cancer, and was present in 98 of 6466 control chromosomes (frequency: 0.015) from healthy individuals (Aoude 2014, Catucci 2014, Garcia 2009, Nguyen-Dumont 2013, Tischkowitz 2012, Teo 2013, Prokofyeva 2012, Wong-Brown 2014, Zheng 2012). The variant was also identified in dbSNP (ID: rs45494092) as “With other allele,” ClinVar (classified as benign by Ambry Genetics, Vantari Genetics, Color Genomics, DGDCHP, PreventionGenetics, Counsyl, Invitae, GeneDx, Pathway Genomics; classified as likely benign by Illumina; classified as uncertain significance by CGLPMCC, PALB2 database), Clinvitae (classified with conflicting interpretations of pathogenicity by ClinVar), LOVD 3.0, databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 42189 (43 homozygous) of 276766 chromosomes at a frequency of 0.01524 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu337 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
12
DANN
Uncertain
0.99
DEOGEN2
Benign
0.025
T;T
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.69
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.53
T;T
MetaRNN
Benign
0.0021
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
.;L
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-1.2
N;N
REVEL
Benign
0.041
Sift
Benign
0.13
T;T
Sift4G
Uncertain
0.018
D;T
Polyphen
0.29
.;B
Vest4
0.065
MPC
0.077
ClinPred
0.0078
T
GERP RS
2.6
Varity_R
0.074
gMVP
0.25

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: rs45494092; hg19: chr16-23646857; COSMIC: COSV55167558; COSMIC: COSV55167558; API