chr16-23635352-C-T

Variant names:

• chr16-23635352-C-T
• rs61755173
• NM_024675.4:c.1194G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_024675.4(PALB2):​c.1194G>A​(p.Val398Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,613,992 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:28
• Conservation: PhyloP100: 1.45

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 16-23635352-C-T is Benign according to our data. Variant chr16-23635352-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126592.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6, Likely_benign=12}. Variant chr16-23635352-C-T is described in Lovd as [Likely_benign]. Variant chr16-23635352-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1194G>A	p.Val398Val	synonymous_variant	Exon 4 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1194G>A	p.Val398Val	synonymous_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.000985 AC: 150 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000741 AC: 186 AN: 250886 Hom.: 0 AF XY: 0.000745 AC XY: 101 AN XY: 135610

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00152 AC: 2227 AN: 1461664 Hom.: 2 Cov.: 32 AF XY: 0.00147 AC XY: 1069 AN XY: 727148

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.00187

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000832 AC XY: 62 AN XY: 74494

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.000945

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:28

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:11

Jan 12, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PALB2: BP4, BP7 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 25, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: Variant Summary: The c.1194G>A (p.Val398=) in PALB2 gene is a synonymous change that involves a non-conserved nucleotide with a prediction of being a "disease-causing" by mutation taster. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at an overall allele frequency of 0.073% (88/121172 chrs tested), mainly in individuals of European descent (0.1154%; 77/66698 chrs tested). The observed frequency exceeds the maximum expected allele frequency for a pathogenic PALB2 variant (0.015%), suggesting that it is a common polymorphism. Based on the published reports, the variant of interest was found in affected individuals as well as in unaffected controls without personal or family history of cancer. Lastly, the variant has been reported as Benign by multiple reputable database/clinical laboratories. Taken together, the variant was classified as Benign. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:5

Nov 01, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 26, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:5

Apr 13, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 08, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 16, 2014

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. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1 Benign:3

May 28, 2019

Mendelics

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

- -

Mar 06, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group N Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Breast and/or ovarian cancer Benign:1

Apr 25, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: 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: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 p.Val398= variant was identified in 10 of 7040 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancers of Spanish, Italian, German, and Australian nationalities and was present in 9 of 6464 control chromosomes (frequency: 0.001) from healthy individuals (Blanco 2012, Catucci 2014, Hellebrand 2011, Thompson 2015). The variant was also identified in dbSNP (ID: rs61755173) as “with Likely benign, other allele”, in ClinVar and Clinvitae databases as benign by Invitae, GeneDx, PALB2 database and likely benign by Ambry Genetics, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, and Illumina Clinical Services; and identified 2X in the LOVD 3.0 database. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer databases. The variant was identified in the 1000 Genomes Project in 4 of 5000 chromosomes (frequency: 0.0008) and in the NHLBI GO Exome Sequencing Project in 20 of 8600 European American African alleles. In addition, the variant was identified in control databases in 212 of 276616 chromosomes at a frequency of 0.0008 in the following populations: African in 9 of 24030 chromosomes (freq. 0.0004), Latino in 19 of 34416 chromosomes (freq. 0.0006), European Non-Finnish in 170 of 126264 chromosomes (freq. 0.001), Ashkenazi Jewish in 9 of 10148 chromosomes (freq. 0.0009), European Finnish in 1 of 25660 chromosomes (freq. 0.00004), and Other in 4 of 6454 chromosomes (freq. 0.0006) but was not seen in East Asian and South Asian POP populations increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Val398= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.6
DANN	Benign	0.53

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

Other links and lift over

dbSNP: rs61755173; hg19: chr16-23646673; COSMIC: COSV104552868; COSMIC: COSV104552868;