rs249954

Variant names:

• chr16-23629146-G-A
• rs249954
• NM_024675.4:c.2586+58C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-23629146-G-A
• chr16-23629146-G-C
• chr16-23629146-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024675.4(PALB2):​c.2586+58C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,332,896 control chromosomes in the GnomAD database, including 48,750 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7873 hom., cov: 32)
  • Exomes 𝑓: 0.26 (40877 hom.)
• Consequence: PALB2 NM_024675.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.329
• Publications: 38 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-23629146-G-A is Benign according to our data. Variant chr16-23629146-G-A is described in ClinVar as Benign. ClinVar VariationId is 126663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.2586+58C>T		intron	N/A	NP_078951.2
	PALB2	NM_001407296.1		c.2526+58C>T		intron	N/A	NP_001394225.1
	PALB2	NM_001407297.1		c.2514+494C>T		intron	N/A	NP_001394226.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.2586+58C>T		intron	N/A	ENSP00000261584.4
	PALB2	ENST00000568219.5	TSL:1	c.1701+58C>T		intron	N/A	ENSP00000454703.2
	PALB2	ENST00000697384.1		n.2798C>T		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47107 AN: 151840 Hom.: 7832 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.297

GnomAD4 exome AF: 0.259 AC: 305341 AN: 1180936 Hom.: 40877 AF XY: 0.260 AC XY: 156052 AN XY: 601128

African (AFR) AF: 0.444 AC: 12439 AN: 28044

American (AMR) AF: 0.276 AC: 12203 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 5938 AN: 24364

East Asian (EAS) AF: 0.382 AC: 14687 AN: 38446

South Asian (SAS) AF: 0.303 AC: 24395 AN: 80552

European-Finnish (FIN) AF: 0.297 AC: 14894 AN: 50068

Middle Eastern (MID) AF: 0.278 AC: 1451 AN: 5222

European-Non Finnish (NFE) AF: 0.239 AC: 205174 AN: 858864

Other (OTH) AF: 0.277 AC: 14160 AN: 51112

GnomAD4 genome AF: 0.311 AC: 47213 AN: 151960 Hom.: 7873 Cov.: 32 AF XY: 0.314 AC XY: 23300 AN XY: 74284

African (AFR) AF: 0.437 AC: 18112 AN: 41408

American (AMR) AF: 0.291 AC: 4441 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3470

East Asian (EAS) AF: 0.365 AC: 1888 AN: 5166

South Asian (SAS) AF: 0.311 AC: 1496 AN: 4810

European-Finnish (FIN) AF: 0.308 AC: 3246 AN: 10550

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16153 AN: 67984

Other (OTH) AF: 0.304 AC: 639 AN: 2104

Alfa AF: 0.265 Hom.: 13872

Bravo AF: 0.315

Asia WGS AF: 0.352 AC: 1225 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Breast-ovarian cancer, familial, susceptibility to, 5 (1)
-	-	1	Familial cancer of breast (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.52
PhyloP100		0.33
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: rs249954; hg19: chr16-23640467; COSMIC: COSV55164558;