chr16-23635649-A-G

Variant names:

• chr16-23635649-A-G
• rs180177095
• NM_024675.4:c.897T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_024675.4(PALB2):​c.897T>C​(p.Ser299Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,966 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.72
• Publications: 1 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-23635649-A-G is Benign according to our data. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776. Variant chr16-23635649-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 126776.
• BP7: Synonymous conserved (PhyloP=1.72 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.897T>C	p.Ser299Ser	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.897T>C	p.Ser299Ser	synonymous_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251340 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000616

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461768 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727192

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15270

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: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

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

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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. -

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. -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2018

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. -

not provided Benign:2

Sep 17, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Mar 11, 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. -

May 23, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group N Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

May 18, 2017

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 and/or ovarian cancer Benign:1

Jul 24, 2020

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

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	-0.85
CADD	Benign	2.8
DANN	Benign	0.64
PhyloP100		1.7

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: rs180177095; hg19: chr16-23646970;