Variant 16-23624049-C-T details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011090875).

BP6

Variant 16-23624049-C-T is Benign according to our data. Variant chr16-23624049-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 126682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624049-C-T is described in Lovd as [Benign]. Variant chr16-23624049-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.2794G>A	p.Val932Met	missense_variant	8/13	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.2794G>A	p.Val932Met	missense_variant	8/13	1	NM_024675.4	ENSP00000261584	P1
	ENST00000561764.1 linkuse as main transcript	n.569C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.00433

AC:

659

AN:

152102

Hom.:

5

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.000990

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.0199

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00523

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00517

AC:

1296

AN:

250912

Hom.:

4

AF XY:

0.00522

AC XY:

709

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.00378

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.0167

Gnomad NFE exome

AF:

0.00660

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00478

AC:

6964

AN:

1455698

Hom.:

24

Cov.:

30

AF XY:

0.00472

AC XY:

3423

AN XY:

724528

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00190

Gnomad4 ASJ exome

AF:

0.00471

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000998

Gnomad4 FIN exome

AF:

0.0147

Gnomad4 NFE exome

AF:

0.00507

Gnomad4 OTH exome

AF:

0.00390

GnomAD4 genome

AF:

0.00433

AC:

659

AN:

152220

Hom.:

5

Cov.:

32

AF XY:

0.00486

AC XY:

362

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000987

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.0199

Gnomad4 NFE

AF:

0.00523

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00502

Hom.:

5

Bravo

AF:

0.00296

TwinsUK

AF:

0.00512

AC:

19

ALSPAC

AF:

0.00441

AC:

17

ESP6500AA

AF:

0.00114

AC:

5

ESP6500EA

AF:

0.00593

AC:

51

ExAC

AF:

0.00586

AC:

712

Asia WGS

AF:

0.00173

AC:

6

AN:

3478

EpiCase

AF:

0.00480

EpiControl

AF:

0.00486

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:30Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 17, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Sep 18, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Carlos Vaccaro, Marc Tischkowitz, Melissa DeRycke. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PALB2: BP4, BS2 -

not specified

Benign:6Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2016	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely 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	Eurofins Ntd Llc (ga)	Apr 03, 2018	- -

Hereditary cancer-predisposing syndrome

Benign:6

Likely 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	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 05, 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	Color Diagnostics, LLC DBA Color Health	Nov 26, 2014	- -

Familial cancer of breast

Benign:4

Likely benign, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 02, 2022

- -

Fanconi anemia complementation group N

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Breast-ovarian cancer, familial, susceptibility to, 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

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.Val932Met variant was identified in 60 of 9444 proband chromosomes (frequency: 0.006) from individuals or families with breast, ovarian and prostate cancer and was present in 69 of 12422 control chromosomes (frequency: 0.006) from healthy individuals (Thompson_2015_26283626, Rahman_2007_17200668, Erkko_2007_17287723, Bogdanova_2011_21165770, Wong_2011_21409391, Kuusisto_2011_21356067, Garcia_2009_18302019, Aoude_2014_24949998, Ding_2011_20927582, Prokofyeva_2012_22310028, Hofstatter_2011_21365267, Papi_2010_19763884, Pakkanen_2009_20003494). The variant was also identified in the following databases: dbSNP (ID: rs45624036) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar (12x, as benign GeneDx, Invitae, Prevention Genetics, ARUP, Ambry Genetics, Pathway Genetics, PALB2 database, and as likely benign by Cancer Genetics, Illumina, Institute for Biomarker; and ITMI with no indication of clinical significance), Clinvitae (4x, as benign with conflicting pathogenicity), LOVD 3.0 (18x), Zhejiang Colon Cancer Database (4x, as benign with conflicting pathogenicity). The variant was not identified in Cosmic and MutDB, databases. The variant was identified in control databases in 1441 of 276692 chromosomes (4 homozygous) at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 31 of 23944 chromosomes (freq: 0.001295), â€šÃ„ÃºOtherâ€šÃ„Ã¹ in 30 of 6452 chromosomes (freq: 0.00465), Latino in 63 of 34386 chromosomes (freq: 0.001832), European Non-Finnish in 814 of 126400 chromosomes (freq: 0.00644), Ashkenazi Jewish in 43 of 10130 chromosomes (freq: 0.004245), European Finnish in 428 of 25784 chromosomes (freq: 0.0166), and South Asian in 32 of 30744 chromosomes (freq: 0.001041); while the variant was not observed in the East Asian, populations. The p.Val932Met residue is not 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 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Familial ovarian cancer

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PALB2 p.Val932Met variant was identified in 60 of 9444 proband chromosomes (frequency: 0.006) from individuals or families with breast, ovarian and prostate cancer and was present in 69 of 12422 control chromosomes (frequency: 0.006) from healthy individuals (Thompson_2015_26283626, Rahman_2007_17200668, Erkko_2007_17287723, Bogdanova_2011_21165770, Wong_2011_21409391, Kuusisto_2011_21356067, Garcia_2009_18302019, Aoude_2014_24949998, Ding_2011_20927582, Prokofyeva_2012_22310028, Hofstatter_2011_21365267, Papi_2010_19763884, Pakkanen_2009_20003494). The variant was also identified in the following databases: dbSNP (ID: rs45624036) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar (12x, as benign GeneDx, Invitae, Prevention Genetics, ARUP, Ambry Genetics, Pathway Genetics, PALB2 database, and as likely benign by Cancer Genetics, Illumina, Institute for Biomarker; and ITMI with no indication of clinical significance), Clinvitae (4x, as benign with conflicting pathogenicity), LOVD 3.0 (18x), Zhejiang Colon Cancer Database (4x, as benign with conflicting pathogenicity). The variant was not identified in Cosmic and MutDB, databases. The variant was identified in control databases in 1441 of 276692 chromosomes (4 homozygous) at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 31 of 23944 chromosomes (freq: 0.001295), â€šÃ„ÃºOtherâ€šÃ„Ã¹ in 30 of 6452 chromosomes (freq: 0.00465), Latino in 63 of 34386 chromosomes (freq: 0.001832), European Non-Finnish in 814 of 126400 chromosomes (freq: 0.00644), Ashkenazi Jewish in 43 of 10130 chromosomes (freq: 0.004245), European Finnish in 428 of 25784 chromosomes (freq: 0.0166), and South Asian in 32 of 30744 chromosomes (freq: 0.001041); while the variant was not observed in the East Asian, populations. The p.Val932Met residue is not 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 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.40

T

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

24

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

T;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.82

D

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.85

T

MutationAssessor

Uncertain

2.5

.;M

MutationTaster

Benign

0.72

D

PrimateAI

Benign

0.46

T

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.13

Sift

Benign

0.11

T;T

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

.;D

Vest4

0.62

MVP

0.65

MPC

0.35

ClinPred

0.021

T

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.085

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

16-23624049-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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