rs141458731

Variant names:

• chr16-23630019-G-A
• rs141458731
• NM_024675.4:c.2135C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-23630019-G-A
• chr16-23630019-G-C
• chr16-23630019-G-T

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.2135C>T​(p.Ala712Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,614,106 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A712P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: -1.29
• Publications: 22 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 (MetaRNN=0.010232568).
• BP6: Variant 16-23630019-G-A is Benign according to our data. Variant chr16-23630019-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000192 (281/1461880) while in subpopulation MID AF = 0.0052 (30/5768). AF 95% confidence interval is 0.00374. There are 2 homozygotes in GnomAdExome4. There are 143 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.2135C>T	p.Ala712Val	missense	Exon 5 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.2075C>T	p.Ala692Val	missense	Exon 4 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.2135C>T	p.Ala712Val	missense	Exon 5 of 12	NP_001394226.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.2135C>T	p.Ala712Val	missense	Exon 5 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.1250C>T	p.Ala417Val	missense	Exon 5 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.2141C>T	p.Ala714Val	missense	Exon 5 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000294 AC: 74 AN: 251492 AF XY: 0.000338

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000316

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000192 AC: 281 AN: 1461880 Hom.: 2 Cov.: 32 AF XY: 0.000197 AC XY: 143 AN XY: 727240

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.000148 AC: 165 AN: 1111998

Other (OTH) AF: 0.000364 AC: 22 AN: 60396

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74424

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.000719 AC: 11 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000382 Hom.: 1

Bravo AF: 0.000268

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Hereditary cancer-predisposing syndrome (7)
-	-	6	not provided (6)
-	-	5	Familial cancer of breast (5)
-	-	3	not specified (3)
-	-	1	Breast-ovarian cancer, familial, susceptibility to, 5 (1)
-	-	1	Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 (1)
-	-	1	Fanconi anemia complementation group N (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.12
DANN	Benign	0.84
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N
PhyloP100		-1.3
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.041
Sift	Benign	0.13	T
Sift4G	Benign	0.30	T
Polyphen		0.017	B
Vest4		0.074
MVP		0.23
MPC		0.053
ClinPred		0.0077	T
GERP RS		-8.6
Varity_R		0.022
gMVP		0.11
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: rs141458731; hg19: chr16-23641340; COSMIC: COSV99849032;