rs57605939

chr16-23635917-G-Achr16-23635917-G-Cchr16-23635917-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_024675.4(PALB2):c.629C>T(p.Pro210Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,614,072 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. P210A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (93 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (98 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:21 O:1
• Conservation: PhyloP100: 0.357

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025817156).
• BP6: Variant 16-23635917-G-A is Benign according to our data. Variant chr16-23635917-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126761.We mark this variant Likely_benign, oryginal submissions are: {Benign=12, Likely_benign=2, not_provided=1, Uncertain_significance=1}. Variant chr16-23635917-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.066 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.629C>T	p.Pro210Leu	missense_variant	4/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.629C>T	p.Pro210Leu	missense_variant	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2942 AN: 152088 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00708

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00477 AC: 1199 AN: 251404 Hom.: 33 AF XY: 0.00364 AC XY: 494 AN XY: 135886

Gnomad AFR exome AF: 0.0655

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00197 AC: 2879 AN: 1461864 Hom.: 98 Cov.: 33 AF XY: 0.00169 AC XY: 1229 AN XY: 727234

Gnomad4 AFR exome AF: 0.0703

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00454

GnomAD4 genome AF: 0.0195 AC: 2969 AN: 152208 Hom.: 93 Cov.: 32 AF XY: 0.0192 AC XY: 1427 AN XY: 74424

Gnomad4 AFR AF: 0.0681

Gnomad4 AMR AF: 0.00707

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00385 Hom.: 22

Bravo AF: 0.0223

ESP6500AA AF: 0.0649 AC: 285

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00618 AC: 750

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:21 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 26, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	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. -
Likely benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2014	- -

Familial cancer of breast Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Benign, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24728327) -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 11, 2019

- -

Fanconi anemia complementation group N Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PALB2 p.Pro210Leu variant was identified in 65 of 10554 proband chromosomes (frequency: 0.006) from individuals or families with breast cancer and was present in 37 of 8955 control chromosomes (frequency: 0.0005) from healthy individuals (Rahman_2007_17200668, Garcia_2009_18302019, Ding_2011_21113654, Zheng_2012_21932393, Tischkowitz_2012_22241545, Thompson_2015_26283626). The variant was also identified in the following databases: dbSNP (ID: rs57605939) as “With other allele”, ClinVar (8x, as benign by Invitae, Ambry, EGL Genetic, Color Genomics, Illumina, Pathway Genomics, PALB2 database, 2x as likely benign, by Cancer Genetics, Institute for Biomarker, 1x as uncertain significant by ITMI), Clinvitae (3x as benign and 3x with conflicting interpretations of pathogenicity by ClinVar and EmvClass), LOVD 3.0 (5x). The variant was not identified in Cosmic, MutDB, and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 1750 of 277182 chromosomes (51 homozygous) at a frequency of 0.006 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1618 of 24022 chromosomes (freq: 0.07), other in 13 of 6468 chromosomes (freq: 0.002), Latino in 105 of 34420 chromosomes (freq: 0.003), European Non-Finnish in 10 of 126682 chromosomes (freq: 0.00008), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), and South Asian in 3 of 30782 chromosomes (freq: 0.0001), while the variant was not observed in the East Asian, European Finnish, populations. The p.Pro210Leu residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 this variant meets our laboratory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	5.1
Dann	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.096
Sift	Benign	0.13	T
Sift4G	Benign	0.79	T
Polyphen		0.021	B
Vest4		0.11
MVP		0.31
MPC		0.059
ClinPred		0.0056	T
GERP RS		0.37
Varity_R		0.033
gMVP		0.16

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

Other links and lift over

dbSNP: rs57605939; hg19: chr16-23647238; COSMIC: COSV55166568; COSMIC: COSV55166568;