chr16-23629826-G-A

Variant names:

• chr16-23629826-G-A
• rs45508997
• NM_024675.4:c.2328C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_024675.4(PALB2):​c.2328C>T​(p.Phe776Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.169
• Publications: 7 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-23629826-G-A is Benign according to our data. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629826-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 225863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.169 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2328C>T	p.Phe776Phe	synonymous_variant	Exon 5 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2328C>T	p.Phe776Phe	synonymous_variant	Exon 5 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251440 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727238

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112006

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3

Mar 23, 2015

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. -

Nov 15, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Familial cancer of breast Benign:3

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Jun 01, 2015

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

not provided Benign:2

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

- -

not specified Benign:1

Apr 27, 2016

GeneDx

Significance: Likely 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. -

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.0
DANN	Benign	0.48
PhyloP100		-0.17

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: rs45508997; hg19: chr16-23641147; COSMIC: COSV55164588;