chr16-23636314-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_024675.4(PALB2):c.232G>A(p.Val78Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,609,794 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:15

Conservation

PhyloP100: 0.206

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 Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07516721).

BP6

Variant 16-23636314-C-T is Benign according to our data. Variant chr16-23636314-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126647.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=12, Benign=1, Uncertain_significance=1}. Variant chr16-23636314-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4 link	c.232G>A	p.Val78Ile	missense_variant	Exon 4 of 13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 link	c.232G>A	p.Val78Ile	missense_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

151812

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000221

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000114

AC:

AN:

246636

Hom.:

AF XY:

0.000142

AC XY:

AN XY:

133496

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000243

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000187

AC:

272

AN:

1457982

Hom.:

Cov.:

AF XY:

0.000192

AC XY:

139

AN XY:

725102

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000235

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000112

AC:

AN:

151812

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74130

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22241545, 23935836, 24949998, 26315354, 26564480, 26283626, 28717660, 28051113, 18302019, 26306225, 29458332, 31586400, 31636395) -

May 13, 2019

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke. -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PALB2: BP4 -

Sep 24, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast

Benign:4

Dec 20, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered 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]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2015

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

Apr 09, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Mar 27, 2019

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 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 08, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified

Benign:2

Oct 13, 2023

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.232G>A (p.Val78Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 257942 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 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.232G>A has been reported in the literature in individuals affected with HBOC or related cancer phenotypes (example, Bhai_2021, Blanco 2013, Damiola 2015, Thompson 2015, Tischkowitz 2012, Castellanos 2017), however, with limited information (i.e. lack of co-occurrence and/or cosegregation data). Moreover, the variant has been also reported in unaffected controls in some studies (Damiola 2015, Ramus 2015). One publication, which focuses on a family that has a history of melanoma, indicates the variant of interest to not segregate with disease (Aoude 2014); i.e. multiple family members are affected with melanomas that do not carry the variant of interest, along with unaffected family members carrying the variant. At least two publications report experimental evidence evaluating an impact on protein function (Rodrigue_2019, Wiltshire_2019). These results showed no damaging effect of this variant on BRCA1 and BRCA2 interaction and Homology directed repair activity (HDR). The following publications have been ascertained in the context of this evaluation (PMID: 24949998, 34326862, 23935836, 28051113, 26564480, 26315354, 31586400, 22241545, 31636395, 26283626). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (Likely benign, n=10, VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PALB2-related disorder

Benign:1

Jun 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Breast and/or ovarian cancer

Benign:1

Oct 27, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 p.Val78Ile variant was identified in 5 of 6906 proband chromosomes (frequency: 0.0007) from Spanish, Australian, Danish and American individuals or families with HBOC (BRCA1/BRCA2 negative breast cancers (with/without pancreatic cancer in the family)) or familial melanoma (Tischkowitz 2012, Thompson 2015, Blanco 2013, Aoude 2014). Segregation analysis in the familial melanoma study did not show cosegregation with disease, with 2 of 4 affected members carrying the variant. The variant was also identified in dbSNP (ID: rs515726085) as â€šÃ„Ãºotherâ€šÃ„Ã¹, ClinVar (classified as uncertain significance by GeneDx, Invitae, PALB2 database, and likely benign by Ambry Genetics and Peter MacCallum Cancer Center Study), Clinvitae (with conflicting interpretations of pathogenicity) and (LOVD 3.0 (4X); and was not identified in Cosmic, MutDB, and Zhejiang Colon Cancer Database databases. The variant was identified in control databases in 30 (1 homozygous) of 272762 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Val78 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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

0.070

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.58

CADD

Benign

2.1

DANN

Benign

0.32

DEOGEN2

Benign

0.10

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.46

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.075

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.45

N;.

REVEL

Benign

0.0040

Sift

Benign

0.23

T;.

Sift4G

Benign

0.36

T;.

Polyphen

0.0090

B;.

Vest4

0.067

MVP

0.30

MPC

0.047

ClinPred

0.015

GERP RS

1.2

Varity_R

0.030

gMVP

0.011

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