rs80291632

Variant names:

• chr16-23636392-T-G
• rs80291632
• NM_024675.4:c.212-58A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-23636392-T-G
• chr16-23636392-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024675.4(PALB2):​c.212-58A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,180,030 control chromosomes in the GnomAD database, including 553 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (62 hom., cov: 32)
  • Exomes 𝑓: 0.029 (491 hom.)
• Consequence: PALB2 NM_024675.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.160
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-23636392-T-G is Benign according to our data. Variant chr16-23636392-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0221 (3360/152190) while in subpopulation NFE AF = 0.0298 (2028/68000). AF 95% confidence interval is 0.0287. There are 62 homozygotes in GnomAd4. There are 1641 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 62 AR,AD gene

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.212-58A>C		intron	N/A	NP_078951.2
	PALB2	NM_001407296.1		c.152-58A>C		intron	N/A	NP_001394225.1
	PALB2	NM_001407297.1		c.212-58A>C		intron	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.212-58A>C		intron	N/A	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.-674-58A>C		intron	N/A	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.218-58A>C		intron	N/A	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3365 AN: 152072 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.00592

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0288

GnomAD4 exome AF: 0.0289 AC: 29699 AN: 1027840 Hom.: 491 AF XY: 0.0289 AC XY: 14989 AN XY: 517932

African (AFR) AF: 0.00503 AC: 115 AN: 22882

American (AMR) AF: 0.0175 AC: 426 AN: 24328

Ashkenazi Jewish (ASJ) AF: 0.0358 AC: 752 AN: 20978

East Asian (EAS) AF: 0.0000904 AC: 3 AN: 33198

South Asian (SAS) AF: 0.0265 AC: 1556 AN: 58638

European-Finnish (FIN) AF: 0.0202 AC: 800 AN: 39516

Middle Eastern (MID) AF: 0.0493 AC: 157 AN: 3182

European-Non Finnish (NFE) AF: 0.0315 AC: 24606 AN: 780386

Other (OTH) AF: 0.0287 AC: 1284 AN: 44732

GnomAD4 genome AF: 0.0221 AC: 3360 AN: 152190 Hom.: 62 Cov.: 32 AF XY: 0.0220 AC XY: 1641 AN XY: 74432

African (AFR) AF: 0.00590 AC: 245 AN: 41520

American (AMR) AF: 0.0253 AC: 387 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 161 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.0238 AC: 115 AN: 4828

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10592

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0298 AC: 2028 AN: 68000

Other (OTH) AF: 0.0285 AC: 60 AN: 2106

Alfa AF: 0.0228 Hom.: 4

Bravo AF: 0.0224

Asia WGS AF: 0.00782 AC: 28 AN: 3466

ClinVar

ClinVar submissions

Significance: Benign/Likely 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)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.15
DANN	Benign	0.71
PhyloP100		-0.16
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: rs80291632; hg19: chr16-23647713; COSMIC: COSV104552834;