rs515726053

Variant names:

• chr16-23603112-T-G
• rs515726053
• NM_024675.4:c.*347A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_024675.4(PALB2):​c.*347A>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 320,938 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: PALB2 NM_024675.4 downstream_gene
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Ambry Genetics
• PALB2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-23603112-T-G is Benign according to our data. Variant chr16-23603112-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 126568.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00123 (188/152338) while in subpopulation AFR AF = 0.00438 (182/41586). AF 95% confidence interval is 0.00386. There are 0 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.*347A>C		downstream_gene	N/A	NP_078951.2
	PALB2	NM_001407296.1		c.*347A>C		downstream_gene	N/A	NP_001394225.1
	PALB2	NM_001407297.1		c.*347A>C		downstream_gene	N/A	NP_001394226.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.*347A>C		downstream_gene	N/A	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.*347A>C		downstream_gene	N/A	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.*347A>C		downstream_gene	N/A	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.000478

GnomAD4 exome AF: 0.000160 AC: 27 AN: 168600 Hom.: 0 Cov.: 0 AF XY: 0.000167 AC XY: 14 AN XY: 83774

African (AFR) AF: 0.00354 AC: 22 AN: 6216

American (AMR) AF: 0.000151 AC: 1 AN: 6602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7010

East Asian (EAS) AF: 0.00 AC: 0 AN: 15110

South Asian (SAS) AF: 0.00 AC: 0 AN: 14356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 103428

Other (OTH) AF: 0.000358 AC: 4 AN: 11184

GnomAD4 genome AF: 0.00123 AC: 188 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74484

African (AFR) AF: 0.00438 AC: 182 AN: 41586

American (AMR) AF: 0.000327 AC: 5 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000832 Hom.: 0

Bravo AF: 0.00146

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.79
PhyloP100		1.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs515726053; hg19: chr16-23614433;