NM_024675.4:c.909C>T

Variant names:

• chr16-23635637-G-A
• rs145788619
• NM_024675.4:c.909C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_024675.4(PALB2):​c.909C>T​(p.Leu303Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,614,082 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 0.00098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.149
• Publications: 4 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-23635637-G-A is Benign according to our data. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635637-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 126778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.149 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000985 (150/152290) while in subpopulation AFR AF = 0.00339 (141/41562). AF 95% confidence interval is 0.00294. There are 0 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.909C>T	p.Leu303Leu	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.909C>T	p.Leu303Leu	synonymous_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000291 AC: 73 AN: 251276 AF XY: 0.000236

Gnomad AFR exome AF: 0.00401

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 147 AN: 1461792 Hom.: 0 Cov.: 32 AF XY: 0.0000853 AC XY: 62 AN XY: 727206

African (AFR) AF: 0.00376 AC: 126 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111956

Other (OTH) AF: 0.0000994 AC: 6 AN: 60392

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74480

African (AFR) AF: 0.00339 AC: 141 AN: 41562

American (AMR) AF: 0.000392 AC: 6 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000570 Hom.: 0

Bravo AF: 0.00105

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2019

Genetic Services Laboratory, University of Chicago

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

- -

Nov 23, 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. -

not provided Benign:4

-

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

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

- -

Mar 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 07, 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. -

Familial cancer of breast Benign:4

Mar 31, 2023

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2016

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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. -

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. -

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.Leu303= variant was identified in 2 of 5770 proband chromosomes (frequency: 0.0003) from individuals or families with prostate or breast cancer and was not identified in 520 control chromosomes from healthy individuals (Tischkowitz 2008, Zheng 2012). The variant was also identified in dbSNP (ID: rs145788619) as "With other allele", ClinVar (classified as benign by GeneDx and Invitae; as likely benign by Ambry Genetics, Counsyl, Color Genomics and one other clinical laboratory), and in LOVD 3.0 database (2x). The variant was not identified in Cosmic, MutDB, or the Zhejiang University database. The variant was identified in control databases in 96 of 277112 chromosomes at a frequency of 0.0003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 86 of 24026 chromosomes (freq: 0.004), Latino in 9 of 34418 chromosomes (freq: 0.0003), and European in 1 of 126634 chromosomes (freq: 0.000008); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu303= 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) do not predict a difference in splicing. 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
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.38
DANN	Benign	0.41
PhyloP100		-0.15
Mutation Taster		=100/0	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: rs145788619; hg19: chr16-23646958;