16-23634027-C-A

Variant names:

• chr16-23634027-C-A
• rs249942
• NM_024675.4:c.1684+835G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024675.4(PALB2):​c.1684+835G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.074 in 152,152 control chromosomes in the GnomAD database, including 483 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.074 (483 hom., cov: 32)
• Consequence: PALB2 NM_024675.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.654
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1684+835G>T		intron_variant	Intron 4 of 12	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1684+835G>T		intron_variant	Intron 4 of 12	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.0740 AC: 11251 AN: 152034 Hom.: 483 Cov.: 32

Gnomad AFR AF: 0.0954

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0605

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.0790

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0582

Gnomad OTH AF: 0.0755

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0740 AC: 11261 AN: 152152 Hom.: 483 Cov.: 32 AF XY: 0.0748 AC XY: 5564 AN XY: 74392

African (AFR) AF: 0.0954 AC: 3961 AN: 41522

American (AMR) AF: 0.0603 AC: 921 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 154 AN: 3466

East Asian (EAS) AF: 0.172 AC: 890 AN: 5164

South Asian (SAS) AF: 0.0791 AC: 381 AN: 4818

European-Finnish (FIN) AF: 0.0750 AC: 795 AN: 10596

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0582 AC: 3960 AN: 68004

Other (OTH) AF: 0.0752 AC: 159 AN: 2114

Alfa AF: 0.0399 Hom.: 36

Bravo AF: 0.0744

Asia WGS AF: 0.117 AC: 406 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.7
DANN	Benign	0.51
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

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: rs249942; hg19: chr16-23645348;