16-23635890-T-C

Position:

chr16-23635890-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_024675.4(PALB2):c.656A>G(p.Asp219Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,614,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:9

Conservation

PhyloP100: -0.596

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:

PALB2 (HGNC:):

PALB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012431294).

BP6

Variant 16-23635890-T-C is Benign according to our data. Variant chr16-23635890-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126763.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=5}. Variant chr16-23635890-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.656A>G	p.Asp219Gly	missense_variant	4/13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.656A>G	p.Asp219Gly	missense_variant	4/13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

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:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

251338

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000280

AC:

409

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

194

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000348

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000204

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000255

Hom.:

Bravo

AF:

0.000246

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:2Benign:2

Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Jul 17, 2019	The c.656A>G variant has been reported in multiple individuals with breast cancer (Rahman 2007, Guenard 2010, Blanco 2013, Thompson 2015, Tung 2016), as well as healthy individuals and an individual with breast cancer who also has a BRCA2 pathogenic variant (Dansonka-Mieszkowska 2010, Ramus 2015, Tung 2016). The c.656A>G variant has an overall allele frequency of 0.0002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. -
Likely 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	- -

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 22, 2022	Variant summary: PALB2 c.656A>G (p.Asp219Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 264172 control chromosomes, predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.656A>G has been reported in the literature in multiple affected individuals (including BRCA1/2 negative individuals) with limited information for an independent assessment (such as co-segregation) (example: Blanco_2013, Damiola_2015, Casas-Arozamena_2020). However, It was also observed in unaffected individuals (example: Ramus_2015, Dansonka-Mieszkowska_2010, Kraemer_2019). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence evaluating an impact on protein function has been reported. Thirteen other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=6) or uncertain significance (n=7). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 17, 2021	DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.656A>G, in exon 4 that results in an amino acid change, p.Asp219Gly. This sequence change has been described in the gnomAD database with a frequency of 0.03% in the non-Finnish European subpopulation (dbSNP rs45594034). The p.Asp219Gly change affects a poorly conserved amino acid residue located in a domain of the PALB2 protein that is not known to be functional. The p.Asp219Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously described in individuals with PALB2-associated cancers as well as in individuals without a cancer history (PMID: 21618343, 23448497, 17200668, 20722467, 23935836, 26283626, 26976419, 20122277, 26315354, https://whi.color.com/variant/16-23647211-T-C FLOSSIES database). Due to contrasting evidences and the lack of functional studies, the clinical significance of the p.Asp219Gly change remains unknown at this time. -

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 13, 2024	The PALB2 c.656A>G (p.Asp219Gly) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 19763884 (2010), 23448497 (2013), 23935836 (2013), 26283626 (2015), 26976419 (2016), 33471991 (2021); see also LOVD (https://databases.lovd.nl/shared/variants/PALB2), 35264596 (2022), 35534704 (2022), 37937776 (2023)) and head and neck squamous cell carcinoma (PMID: 28678401 (2017)). This variant has also been identified in at least one reportedly healthy individual (PMID: 20122277 (2010), 26315354 (2015), 33471991 (2021), see also LOVD ((https://databases.lovd.nl/shared/variants/PALB2)). The frequency of this variant in the general population, 0.00033 (42/129110 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2021	In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26283626, 20722467, 26564480, 19763884, 20122277, 21618343, 23448497, 23935836, 17200668, 25186627, 26976419, 25801821, 27621404, 26315354, 27153395, 28779002, 23555315, 29522266, 31422574) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PALB2: BP1, BP4 -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jun 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 31, 2018	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. -

PALB2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2023

The PALB2 c.656A>G variant is predicted to result in the amino acid substitution p.Asp219Gly. This variant has been reported in multiple individuals with a personal and/or family history of pancreatic and breast cancers (Tung et al. 2015. PubMed ID: 25186627; Tung et al. 2016. PubMed ID: 26976419; Blanco et al. 2013. PubMed ID: 23935836; Thompson et al. 2015. PubMed ID: 26283626; Supplementary Table 1, Rahman et al. 2007. PubMed ID: 17200668). It has been reported in a non-cancer cohort and also healthy control individuals (Table 4, Dansonka-Mieszkowska et al. 2010. PubMed ID: 20122277; Table S4, Ramus et al. 2015. PubMed ID: 26315354; Kraemer et al. 2019. PubMed ID: 31422574). It has also been reported in an individual with breast cancer that harbored a pathogenic truncating BRCA2 variant (Table A1 and A2, Study ID BOB20988WB, Tung et al. 2016. PubMed ID: 26976419). This variant is reported in 0.033% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126763/). Although we suspect that this variant is likely benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.48

DANN

Benign

0.39

DEOGEN2

Benign

0.059

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.63

M_CAP

Benign

0.0069

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.46

PrimateAI

Benign

0.19

PROVEAN

Benign

0.81

REVEL

Benign

0.061

Sift

Benign

0.46

Sift4G

Benign

0.50

Polyphen

0.0

Vest4

0.058

MVP

0.23

MPC

0.064

ClinPred

0.014

GERP RS

-5.1

Varity_R

0.023

gMVP

0.11

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