16-23635536-A-G

Position:

chr16-23635536-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

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]

PALB2 links:

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: {Likely_benign=2, not_provided=1, Benign=15, Uncertain_significance=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/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.1010T>C	p.Leu337Ser	missense_variant	4/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.1010T>C	p.Leu337Ser	missense_variant	4/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2215

AN:

152102

Hom.:

Cov.:

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.:

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.:

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.:

Cov.:

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.:

Bravo

AF:

0.0110

TwinsUK

AF:

0.0259

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.00364

AC:

ESP6500EA

AF:

0.0197

AC:

169

ExAC

AF:

0.0142

AC:

1729

Asia WGS

AF:

0.00202

AC:

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 29, 2015	- -

Hereditary cancer-predisposing syndrome

Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 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. -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 12, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 23, 2018	- -

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 07, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Maximiliano Zeballos, Melissa DeRycke. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PALB2: BP4, BS1, BS2 -

Familial cancer of breast

Uncertain:1Benign:4

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 14, 2020

- -

Fanconi anemia complementation group N

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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 â€šÃ„ÃºWith other allele,â€šÃ„Ã¹ 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

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

T;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.53

T;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

.;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over