16-23635890-T-C

Variant names:

• chr16-23635890-T-C
• rs45594034
• NM_024675.4:c.656A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D219D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:12
• Conservation: PhyloP100: -0.596
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 126763.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.656A>G	p.Asp219Gly	missense	Exon 4 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.596A>G	p.Asp199Gly	missense	Exon 3 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.656A>G	p.Asp219Gly	missense	Exon 4 of 12	NP_001394226.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.656A>G	p.Asp219Gly	missense	Exon 4 of 13	ENSP00000261584.4
	PALB2	ENST00000568219.5	TSL:1	c.-230A>G		5_prime_UTR	Exon 4 of 13	ENSP00000454703.2
	PALB2	ENST00000561514.3	TSL:5	c.662A>G	p.Asp221Gly	missense	Exon 4 of 13	ENSP00000460666.3

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152176 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000203 AC: 51 AN: 251338 AF XY: 0.000191

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 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.: 1 Cov.: 33 AF XY: 0.000267 AC XY: 194 AN XY: 727222

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000348 AC: 387 AN: 1111964

Other (OTH) AF: 0.000149 AC: 9 AN: 60394

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74472

African (AFR) AF: 0.0000481 AC: 2 AN: 41576

American (AMR) AF: 0.000720 AC: 11 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:2 Benign:3

May 13, 2019

Leiden Open Variation Database

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.

Jun 01, 2015

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: case-control

Jan 10, 2025

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

Jul 17, 2019

Division of Medical Genetics, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:5

Dec 31, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 03, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 15, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 10, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 + BP4

Sep 24, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP1 c.656A>G, located in exon 4 of the PALB2 gene, is predicted to result in the substitution of aspartic acid by glycine at codon 219, p.(Asp219Gly). This is a missense variant in a gene with low rate of missense variants that are non-functional in relevant assays (BP1). The variant allele was found in 38/118096 alleles, with a filter allele frequency of 0.24% at 99% confidence, within the non-Finnish European population in the gnomAD v2.1.1 database (non-cancer data set) (BS1). To our knowledge, no well-established functional studies have been reported for this variant. It has been reported in multiple cancer-affected individuals (PMID: 17200668, 20722467, 19763884, 21618343, 23935836, 23448497, 26976419, 28779002), as well as in healthy individuals and in a BRCA2 pathogenic variant carrier (20122277, 26315354, 26976419). Based on currently available information, the variant c.656A>G should be considered a likely benign variant.

not specified Uncertain:2 Benign:1

Sep 22, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 17, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1 Benign:2

Aug 13, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PALB2: BP1, BP4

Jan 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

PALB2-related disorder Uncertain:1

Nov 16, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Breast-ovarian cancer, familial, susceptibility to, 5 Uncertain:1

May 12, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer Benign:1

Jan 23, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.48
DANN	Benign	0.39
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.46	N
PhyloP100		-0.60
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.81	N
REVEL	Benign	0.061
Sift	Benign	0.46	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.058
MVP		0.23
MPC		0.064
ClinPred		0.014	T
GERP RS		-5.1
Varity_R		0.023
gMVP		0.11
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs45594034; hg19: chr16-23647211;